ACC inhibitors and uses thereof

ABSTRACT

The present invention provides compounds useful as inhibitors of Acetyl CoA Carboxylase (ACC), compositions thereof, and methods of using the same.

BACKGROUND OF THE INVENTION

Obesity is a health crisis of epic proportions. The health burden ofobesity, measured by quality-adjusted life-years lost per adult, hassurpassed that of smoking to become the most serious, preventable causeof death. In the US, about 34% of adults have obesity, up from 31% in1999 and about 15% in the years 1960 through 1980. Obesity increases therate of mortality from all causes for both men and women at all ages andin all racial and ethnic groups. Obesity also leads to socialstigmatization and discrimination, which decreases quality of lifedramatically. The chronic diseases that result from obesity cost the USeconomy more than $150 billion in weight-related medical bills eachyear. Furthermore, about half of the obese population, and 25% of thegeneral population, have metabolic syndrome, a condition associated withabdominal obesity, hypertension, increased plasma triglycerides,decreased HDL cholesterol, and insulin resistance, which increases therisk for type-2 diabetes (T2DM), stroke and coronary heart disease.[Harwood, Expert Opin. Ther. Targets 9: 267, 2005].

Diet and exercise, even when used in conjunction with the currentpharmacotherapy, do not provide sustainable weight loss needed forlong-term health benefit. Currently, only a few anti-obesity drugs areapproved in the US, the fat absorption inhibitor orlistat (Xenical®),the 5-HT_(2C) antagonist lorcaserin (Belviq®), and the combinationtherapy phentermine/topiramate (Qsymia®)). Unfortunately, poor efficacyand unappealing gastrointestinal side effects limit the use of orlistat.Surgery can be effective but is limited to patients with extremely highbody-bass indices (BMI) and the low throughput of surgery limits theimpact of this modality to about 200 k patients per year. The majorityof obesity drugs in clinical development are designed to reduce caloricintake through central action in the CNS (e.g., anorectics and satietyagents). However, the FDA has taken an unfavorable position againstCNS-active agents, due to their modest efficacy and observed/potentialside-effect profiles.

The continuing and increasing problem of obesity, and the current lackof safe and effective drugs for treating it, highlight the overwhelmingneed for new drugs to treat this condition and its underlying causes.

SUMMARY OF THE INVENTION

It has now been found that compounds of this invention, andpharmaceutically acceptable compositions thereof, are effective asinhibitors of Acetyl-CoA carboxylase (ACC). Such compounds have thegeneral formula I:

or a pharmaceutically acceptable salt thereof, wherein each variable isas defined and described herein.

Compounds of the present invention, and pharmaceutically acceptablecompositions thereof, are useful for treating a variety of diseases,disorders or conditions, associated with regulation of the production oroxidation of fatty acids. Such diseases, disorders, or conditionsinclude those described herein.

Compounds provided by this invention are also useful for the study ofACC enzymes in biological and pathological phenomena; the study ofintracellular signal transduction pathways occurring in lipogenictissues; and the comparative evaluation of new ACC inhibitors or otherregulators of fatty acid levels in vitro or in vivo.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS

1. General Description of Compounds of the Invention:

In certain embodiments, the present invention provides inhibitors ofACC. In some embodiments, such compounds include those of formula I:

or a pharmaceutically acceptable salt thereof, wherein:

-   W is —C(O)—, —C(S)—, or —S(O)₂—;-   Q is —C(O)—, —C(S)—, —S(O)₂—, or N;-   X is —O—, —S—, —NR—, or N;-   Y is C or N;-   Z is C or N;-   R¹ is hydrogen or C₁₋₄ aliphatic, optionally substituted with one or    more halogens, —OR, —SR, —N(R)₂, —N(R)C(O)R, —C(O)N(R)₂,    —N(R)C(O)N(R)₂, —N(R)C(O)OR, —OC(O)N(R)₂, —N(R)SO₂R, —SO₂RN(R)₂,    —C(O)R, —C(O)OR, —OC(O)R, —C(O)OR, —S(O)R, or —SO₂R;-   R² is halogen, —R, —OR, —SR, —N(R)₂, —N(R)C(O)R, —C(O)N(R)₂,    —N(R)C(O)N(R)₂, —N(R)C(O)OR, —OC(O)N(R)₂, —N(R)SO₂R, —SO₂N(R)₂,    —C(O)R, —C(O)OR, —OC(O)R, —S(O)R, or —SO₂R, —B(OR)₂, or Hy, where Hy    is selected from 4-8 membered saturated or partially unsaturated    monocyclic heterocyclic ring having 1-2 heteroatoms independently    selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic    heteroaromatic ring having 1-4 heteroatoms independently selected    from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic    heteroaromatic ring having 1-5 heteroatoms independently selected    from nitrogen, oxygen, or sulfur; wherein R² is not optionally    substituted benzyl; or    -   R¹ and R² are taken together to form an optionally substituted        4-7 membered partially unsaturated carbocyclo-, or heterocyclo-,        benzo-, or 5-6 membered heteroarylo-fused ring;-   each R is independently hydrogen, deuterium, or an optionally    substituted group selected from C₁₋₆ aliphatic, a 3-8 membered    saturated or partially unsaturated monocyclic carbocyclic ring,    phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring; a 4-8    membered saturated or partially unsaturated monocyclic heterocyclic    ring having 1-2 heteroatoms independently selected from nitrogen,    oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring    having 1-4 heteroatoms independently selected from nitrogen, oxygen,    or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having    1-5 heteroatoms independently selected from nitrogen, oxygen, or    sulfur;-   L¹ is a covalent bond or a 1-6 membered straight or branched    bivalent hydrocarbon chain optionally substituted with R⁵ and    R^(5′);-   L² is a covalent bond or a 1-6 membered straight or branched    bivalent hydrocarbon chain optionally substituted with R⁷ and    R^(7′);-   R³ is halogen, —CN, —OR, —SR, —N(R)₂, —N(R)C(O)R, —C(O)RN(R)₂,    —C(O)N(R)S(O)₂R, —N(R)C(O)N(R)₂, —N(R)C(O)OR, —OC(O)N(R)₂,    —N(R)SO₂R, —SO₂N(R)₂, —C(O)R, —C(O)OR, —OC(O)R, —S(O)R, —SO₂R,    —B(OR)₂, or an optionally substituted ring selected from phenyl or    5-6 membered heteroaryl having 1-4 heteroatoms independently    selected from nitrogen, oxygen, or sulfur;-   R⁴ is hydrogen or a ring selected from a 3-8 membered monocyclic    saturated or partially unsaturated carbocyclic ring, a 4-8 membered    monocyclic saturated or partially unsaturated heterocyclic ring    having 1-2 heteroatoms independently selected from nitrogen, oxygen,    or sulfur, phenyl, an 8-10 membered bicyclic aryl ring, a 5-6    membered monocyclic heteroaryl ring having 1-4 heteroatoms    independently selected from nitrogen, oxygen, or sulfur, or an 8-10    membered bicyclic heteroaryl ring having 1-4 heteroatoms    independently selected from nitrogen, oxygen, or sulfur; wherein    said ring is optionally substituted with n instances of R⁸;-   each of R⁵ and R⁵′ is independently —R, —OR, —SR, —N(R)₂,    —N(R)C(O)R, —C(O)N(R)₂, —N(R)C(O)N(R)₂, —N(R)C(O)OR, —OC(O)N(R)₂,    —N(R)SO₂R, —SO₂N(R)₂, —C(O)R, —C(O)OR, —OC(O)R, —S(O)R, or —SO₂R; or    R⁵ and R^(5′) are taken together to form a cyclopropylenyl,    cyclobutylenyl, or oxetanyl group;-   each of R⁷ and R^(7′) is independently, —R, —OR⁶, —SR, —N(R)₂,    —N(R)C(O)R, —C(O)N(R)₂, —N(R)C(O)N(R)₂, —N(R)C(O)OR, —OC(O)N(R)₂,    —N(R)SO₂R, —SO₂N(R)₂, —C(O)R, —C(O)OR, —OC(O)R, —S(O)R, —SO₂R, or    —B(OR)₂; or R⁷ and R^(7′) are taken together to form a 3-8 membered    saturated or partially unsaturated monocyclic carbocyclic ring, or a    4-8 membered saturated or partially unsaturated monocyclic    heterocyclic ring having 1-2 heteroatoms independently selected from    nitrogen, oxygen, or sulfur;-   R⁶ is —R, —C(O)N(R)₂, or —C(O)R;-   each R⁸ is independently selected from halogen, —R, —OR, —SR, —N(R)₂    or deuterium; and-   n is 0-5.    2. Compounds and Definitions

Compounds of this invention include those described generally above, andare further illustrated by the classes, subclasses, and speciesdisclosed herein. As used herein, the following definitions shall applyunless otherwise indicated. For purposes of this invention, the chemicalelements are identified in accordance with the Periodic Table of theElements, CAS version, Handbook of Chemistry and Physics, 75^(th) Ed.Additionally, general principles of organic chemistry are described in“Organic Chemistry”, Thomas Sorrell, University Science Books,Sausalito: 1999, and “March's Advanced Organic Chemistry”, 5^(th) Ed.,Ed.: Smith, M. B. and March, J., John Wiley & Sons, New York: 2001, theentire contents of which are hereby incorporated by reference.

The term “aliphatic” or “aliphatic group”, as used herein, means astraight-chain (i.e., unbranched) or branched, substituted orunsubstituted hydrocarbon chain that is completely saturated or thatcontains one or more units of unsaturation, or a monocyclic hydrocarbonor bicyclic hydrocarbon that is completely saturated or that containsone or more units of unsaturation, but which is not aromatic (alsoreferred to herein as “carbocycle,” “cycloaliphatic” or “cycloalkyl”),that has a single point of attachment to the rest of the molecule.Unless otherwise specified, aliphatic groups contain 1-6 aliphaticcarbon atoms. In some embodiments, aliphatic groups contain 1-5aliphatic carbon atoms. In other embodiments, aliphatic groups contain1-4 aliphatic carbon atoms. In still other embodiments, aliphatic groupscontain 1-3 aliphatic carbon atoms, and in yet other embodiments,aliphatic groups contain 1-2 aliphatic carbon atoms. In someembodiments, “cycloaliphatic” (or “carbocycle” or “cycloalkyl”) refersto a monocyclic C₃-C₆ hydrocarbon that is completely saturated or thatcontains one or more units of unsaturation, but which is not aromatic,that has a single point of attachment to the rest of the molecule.Suitable aliphatic groups include, but are not limited to, linear orbranched, substituted or unsubstituted alkyl, alkenyl, alkynyl groupsand hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or(cycloalkyl)alkenyl.

The term “lower alkyl” refers to a C₁₋₄ straight or branched alkylgroup. Exemplary lower alkyl groups are methyl, ethyl, propyl,isopropyl, butyl, isobutyl, and tert-butyl.

The term “lower haloalkyl” refers to a C₁₋₄ straight or branched alkylgroup that is substituted with one or more halogen atoms.

The term “heteroatom” means one or more of oxygen, sulfur, nitrogen,phosphorus, or silicon (including, any oxidized form of nitrogen,sulfur, phosphorus, or silicon; the quaternized form of any basicnitrogen or; a substitutable nitrogen of a heterocyclic ring, forexample N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) orNR⁺ (as in N-substituted pyrrolidinyl)).

The term “unsaturated,” as used herein, means that a moiety has one ormore units of unsaturation.

As used herein, the term “bivalent C₁₋₈ (or C₁₋₆) saturated orunsaturated, straight or branched, hydrocarbon chain”, refers tobivalent alkylene, alkenylene, and alkynylene chains that are straightor branched as defined herein.

The term “alkylene” refers to a bivalent alkyl group. An “alkylenechain” is a polymethylene group, i.e., —(CH₂)_(n)—, wherein n is apositive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from1 to 2, or from 2 to 3. A substituted alkylene chain is a polymethylenegroup in which one or more methylene hydrogen atoms are replaced with asubstituent. Suitable substituents include those described below for asubstituted aliphatic group.

The term “alkenylene” refers to a bivalent alkenyl group. A substitutedalkenylene chain is a polymethylene group containing at least one doublebond in which one or more hydrogen atoms are replaced with asubstituent. Suitable substituents include those described below for asubstituted aliphatic group.

As used herein, the term “cyclopropylenyl” refers to a bivalentcyclopropyl group of the following structure:

As used herein, the term “cyclobutylenyl” refers to a bivalentcyclobutyl group of the following structure:

As used herein, the term “oxetanyl” refers to a bivalent oxetanyl groupof the following structure:

The term “halogen” means F, Cl, Br, or I.

The term “aryl” used alone or as part of a larger moiety as in“aralkyl,” “aralkoxy,” or “aryloxyalkyl,” refers to monocyclic orbicyclic ring systems having a total of five to fourteen ring members,wherein at least one ring in the system is aromatic and wherein eachring in the system contains 3 to 7 ring members. The term “aryl” may beused interchangeably with the term “aryl ring.”

The term “aryl” used alone or as part of a larger moiety as in“aralkyl,” “aralkoxy,” or “aryloxyalkyl,” refers to monocyclic andbicyclic ring systems having a total of five to 10 ring members, whereinat least one ring in the system is aromatic and wherein each ring in thesystem contains three to seven ring members. The term “aryl” may be usedinterchangeably with the term “aryl ring”. In certain embodiments of thepresent invention, “aryl” refers to an aromatic ring system whichincludes, but not limited to, phenyl, biphenyl, naphthyl, anthracyl andthe like, which may bear one or more substituents. Also included withinthe scope of the term “aryl,” as it is used herein, is a group in whichan aromatic ring is fused to one or more non-aromatic rings, such asindanyl, phthalimidyl, naphthimidyl, phenanthridinyl, ortetrahydronaphthyl, and the like.

The terms “heteroaryl” and “heteroar-,” used alone or as part of alarger moiety, e.g., “heteroaralkyl,” or “heteroaralkoxy,” refer togroups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms;having 6, 10, or 14 π electrons shared in a cyclic array; and having, inaddition to carbon atoms, from one to five heteroatoms. The term“heteroatom” refers to nitrogen, oxygen, or sulfur, and includes anyoxidized form of nitrogen or sulfur, and any quaternized form of a basicnitrogen. Heteroaryl groups include, without limitation, thienyl,furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl,oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl,thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl,purinyl, naphthyridinyl, and pteridinyl. The terms “heteroaryl” and“heteroar-”, as used herein, also include groups in which aheteroaromatic ring is fused to one or more aryl, cycloaliphatic, orheterocyclyl rings, where the radical or point of attachment is on theheteroaromatic ring. Nonlimiting examples include indolyl, isoindolyl,benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl,benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl,quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl,phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl,tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. Aheteroaryl group may be mono- or bicyclic. The term “heteroaryl” may beused interchangeably with the terms “heteroaryl ring,” “heteroarylgroup,” or “heteroaromatic,” any of which terms include rings that areoptionally substituted. The term “heteroaralkyl” refers to an alkylgroup substituted by a heteroaryl, wherein the alkyl and heteroarylportions independently are optionally substituted.

As used herein, the terms “heterocycle,” “heterocyclyl,” “heterocyclicradical,” and “heterocyclic ring” are used interchangeably and refer toa stable 5- to 7-membered monocyclic or 7-10-membered bicyclicheterocyclic moiety that is either saturated or partially unsaturated,and having, in addition to carbon atoms, one or more, preferably one tofour, heteroatoms, as defined above. When used in reference to a ringatom of a heterocycle, the term “nitrogen” includes a substitutednitrogen. As an example, in a saturated or partially unsaturated ringhaving 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, thenitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as inpyrrolidinyl), or ⁺NR (as in N-substituted pyrrolidinyl).

A heterocyclic ring can be attached to its pendant group at anyheteroatom or carbon atom that results in a stable structure and any ofthe ring atoms can be optionally substituted. Examples of such saturatedor partially unsaturated heterocyclic radicals include, withoutlimitation, tetrahydrofuranyl, tetrahydrothiophenyl pyrrolidinyl,piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl,decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl,diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. Theterms “heterocycle,” “heterocyclyl,” “heterocyclyl ring,” “heterocyclicgroup,” “heterocyclic moiety,” and “heterocyclic radical,” are usedinterchangeably herein, and also include groups in which a heterocyclylring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings,such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, ortetrahydroquinolinyl, where the radical or point of attachment is on theheterocyclyl ring. A heterocyclyl group may be mono- or bicyclic. Theterm “heterocyclylalkyl” refers to an alkyl group substituted by aheterocyclyl, wherein the alkyl and heterocyclyl portions independentlyare optionally substituted.

As used herein, the term “partially unsaturated” refers to a ring moietythat includes at least one double or triple bond. The term “partiallyunsaturated” is intended to encompass rings having multiple sites ofunsaturation, but is not intended to include aryl or heteroarylmoieties, as herein defined.

As described herein, compounds of the invention may contain “optionallysubstituted” moieties. In general, the term “substituted,” whetherpreceded by the term “optionally” or not, means that one or morehydrogens of the designated moiety are replaced with a suitablesubstituent. Unless otherwise indicated, an “optionally substituted”group may have a suitable substituent at each substitutable position ofthe group, and when more than one position in any given structure may besubstituted with more than one substituent selected from a specifiedgroup, the substituent may be either the same or different at everyposition. Combinations of substituents envisioned by this invention arepreferably those that result in the formation of stable or chemicallyfeasible compounds. The term “stable,” as used herein, refers tocompounds that are not substantially altered when subjected toconditions to allow for their production, detection, and, in certainembodiments, their recovery, purification, and use for one or more ofthe purposes disclosed herein.

Suitable monovalent substituents on a substitutable carbon atom of an“optionally substituted” group are independently halogen;—(CH₂)₀₋₄R^(∘); —(CH₂)₀₋₄OR^(∘); —O(CH₂)₀₋₄R^(∘), —O—(CH₂)₀₋₄C(O)OR^(∘);—(CH₂)₀₋₄CH(OR^(∘))₂; —(CH₂)₀₋₄SR^(∘); —(CH₂)₀₋₄Ph, which may besubstituted with R^(∘); —(CH₂)₀₋₄O(CH₂)₀₋₁-Ph which may be substitutedwith R^(∘); —CH═CHPh, which may be substituted with R^(∘);—(CH₂)₀₋₄O(CH₂)₀₋₁-pyridyl which may be substituted with R^(∘); —NO₂;—CN; —N₃; —(CH₂)₀₋₄N(R^(∘))₂; —(CH₂)₀₋₄N(R^(∘))C(O)R^(∘);—N(R^(∘))C(S)R^(∘); —(CH₂)₀₋₄N(R^(∘))C(O)NR^(∘) ₂; —N(R^(∘))C(S)NR^(∘)₂; —(CH₂)₀₋₄N(R^(∘))C(O)OR^(∘); —N(R^(∘))N(R^(∘))C(O)R^(∘);—N(R^(∘))N(R^(∘))C(O)NR^(∘) ₂; —N(R^(∘))N(R^(∘))C(O)OR^(∘);—(CH₂)₀₋₄C(O)R^(∘); —C(S)R^(∘); —(CH₂)₀₋₄C(O)OR^(∘);—(CH₂)₀₋₄C(O)SR^(∘); —(CH₂)₀₋₄C(O)OSiR^(∘) ₃; —(CH₂)₀₋₄OC(O)R^(∘);—OC(O)(CH₂)₀₋₄SR—, SC(S)SR^(∘); —(CH₂)₀₋₄SC(O)R^(∘); —(CH₂)₀₋₄C(O)NR^(∘)₂; —C(S)NR^(∘) ₂; —C(S)SR^(∘); —SC(S)SR^(∘), —(CH₂)₀₋₄OC(O)NR^(∘) ₂;—C(O)N(OR^(∘))R^(∘); —C(O)C(O)R^(∘); —C(O)CH₂C(O)R^(∘);—C(NOR^(∘))R^(∘); —(CH₂)₀₋₄SSR^(∘); —(CH₂)₀₋₄S(O)₂R^(∘);—(CH₂)₀₋₄S(O)₂OR^(∘); —(CH₂)₀₋₄OS(O)₂R^(∘); —S(O)₂NR^(∘) ₂;—(CH₂)₀₋₄S(O)R^(∘); —N(R^(∘))S(O)₂NR^(∘) ₂; —N(R^(∘))S(O)₂R^(∘);—N(OR^(∘))R^(∘); —C(NH)NR^(∘) ₂; —P(O)₂R^(∘); —P(O)R^(∘) ₂; —OP(O)R^(∘)₂; —OP(O)(OR^(∘))₂; SiR^(∘) ₃; —(C₁₋₄ straight orbranched)alkylene)O—N(R^(∘) ₂; or —(C₁₋₄ straight orbranched)alkylene)C(O)O—N(R^(∘))₂, wherein each R^(∘) may be substitutedas defined below and is independently hydrogen, C₁₋₆ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, —CH₂-(5-6 membered heteroaryl ring), or a 5-6-memberedsaturated, partially unsaturated, or aryl ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or,notwithstanding the definition above, two independent occurrences ofR^(∘), taken together with their intervening atom(s), form a3-12-membered saturated, partially unsaturated, or aryl mono- orbicyclic ring having 0-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, which may be substituted as defined below.

Suitable monovalent substituents on R^(∘) (or the ring formed by takingtwo independent occurrences of R^(∘) together with their interveningatoms), are independently halogen, —(CH₂)₀₋₂R^(●), -(haloR^(●)),—(CH₂)₀₋₂OH, —(CH₂)₀₋₂OR^(●), —(CH₂)₀₋₂CH(OR^(●))₂; —O(haloR^(●)), —CN,—N₃, —(CH₂)₀₋₂C(O)R^(●), —(CH₂)₀₋₂C(O)OH, —(CH₂)₀₋₂C(O)OR^(●),—(CH₂)₀₋₂SR^(●), —(CH₂)₀₋₂SH, —(CH₂)₀₋₂NH₂, —(CH₂)₀₋₂NHR^(●),—(CH₂)₀₋₂NR^(●) ₂, —NO₂, —SiR^(●) ₃, —OSiR^(●) ₃, —C(O)SR^(●), —(C₁₋₄straight or branched alkylene)C(O)OR^(●), or —SSR^(●) wherein each R^(●)is unsubstituted or where preceded by “halo” is substituted only withone or more halogens, and is independently selected from C₁ aliphatic,—CH₂Ph, —O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partiallyunsaturated, or aryl ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur. Suitable divalent substituents on asaturated carbon atom of R^(∘) include ═O and ═S.

Suitable divalent substituents on a saturated carbon atom of an“optionally substituted” group include the following: ═O, ═S, ═NNR*₂,═NNHC(O)R*, ═NNHC(O)OR*, ═NNHS(O)₂R*, ═NR*, ═NOR*, —O(C(R*₂))₂₋₃O—, or—S(C(R*₂))₂₋₃S—, wherein each independent occurrence of R* is selectedfrom hydrogen, C₁₋₆ aliphatic which may be substituted as defined below,or an unsubstituted 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur. Suitable divalent substituents that are bound tovicinal substitutable carbons of an “optionally substituted” groupinclude: —O(CR*₂)₂₋₃O—, wherein each independent occurrence of R* isselected from hydrogen, C₁₋₆ aliphatic which may be substituted asdefined below, or an unsubstituted 5-6-membered saturated, partiallyunsaturated, or aryl ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur.

Suitable substituents on the aliphatic group of R* include halogen,—R^(●), -(haloR^(●)), —OH, —OR^(●), —O(haloR^(●)), —CN, —C(O)OH,—C(O)OR^(●), —NH₂, —NHR^(●), —NR^(●) ₂, or —NO₂, wherein each R^(●) isunsubstituted or where preceded by “halo” is substituted only with oneor more halogens, and is independently C₁₋₄ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur.

Suitable substituents on a substitutable nitrogen of an “optionallysubstituted” group include —R^(†), —NR^(†) ₂, —C(O)R^(†), —C(O)OR^(†),—C(O)C(O)R^(†), —C(O)CH₂C(O)R^(†), —S(O)₂R^(†), —S(O)₂NR^(†) ₂,—C(S)NR^(†) ₂, —C(NH)NR^(†) ₂, or —N(R^(†))S(O)₂R^(†); wherein eachR^(†) is independently hydrogen, C₁₋₆ aliphatic which may be substitutedas defined below, unsubstituted —OPh, or an unsubstituted 5-6-memberedsaturated, partially unsaturated, or aryl ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or,notwithstanding the definition above, two independent occurrences ofR^(†), taken together with their intervening atom(s) form anunsubstituted 3-12-membered saturated, partially unsaturated, or arylmono- or bicyclic ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur.

Suitable substituents on the aliphatic group of R^(●) are independentlyhalogen, —R^(●), -(haloR^(●)), —OH, —OR^(●), —O(haloR^(●)), —CN,—C(O)OH, —C(O)OR^(●), —NH₂, —NHR^(●), —NR^(●) ₂, or —NO₂, wherein eachR^(●) is unsubstituted or where preceded by “halo” is substituted onlywith one or more halogens, and is independently C₁₋₄ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur.

As used herein, the term “pharmaceutically acceptable salt” refers tothose salts which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like, andare commensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well known in the art. For example, S. M. Berge etal., describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein byreference. Pharmaceutically acceptable salts of the compounds of thisinvention include those derived from suitable inorganic and organicacids and bases. Examples of pharmaceutically acceptable, nontoxic acidaddition salts are salts of an amino group formed with inorganic acidssuch as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuricacid and perchloric acid or with organic acids such as acetic acid,oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid ormalonic acid or by using other methods used in the art such as ionexchange. Other pharmaceutically acceptable salts include adipate,alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate,borate, butyrate, camphorate, camphorsulfonate, citrate,cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,formate, fumarate, glucoheptonate, glycerophosphate, gluconate,hemisulfate, heptanoate, hexanoate, hydroiodide,2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate,propionate, stearate, succinate, sulfate, tartrate, thiocyanate,p-toluenesulfonate, undecanoate, valerate salts, and the like.

Salts derived from appropriate bases include alkali metal, alkalineearth metal, ammonium and N⁺(C₁₋₄alkyl)₄ salts. Representative alkali oralkaline earth metal salts include sodium, lithium, potassium, calcium,magnesium, and the like. Further pharmaceutically acceptable saltsinclude, when appropriate, nontoxic ammonium, quaternary ammonium, andamine cations formed using counterions such as halide, hydroxide,carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and arylsulfonate.

Unless otherwise stated, structures depicted herein are also meant toinclude all isomeric (e.g., enantiomeric, diastereomeric, and geometric(or conformational)) forms of the structure; for example, the R and Sconfigurations for each asymmetric center, Z and E double bond isomers,and Z and E conformational isomers. Therefore, single stereochemicalisomers as well as enantiomeric, diastereomeric, and geometric (orconformational) mixtures of the present compounds are within the scopeof the invention. Unless otherwise stated, all tautomeric forms of thecompounds of the invention are within the scope of the invention.Additionally, unless otherwise stated, structures depicted herein arealso meant to include compounds that differ only in the presence of oneor more isotopically enriched atoms. For example, compounds having thepresent structures including the replacement of hydrogen by deuterium ortritium, or the replacement of a carbon by a ¹³C- or ¹⁴C-enriched carbonare within the scope of this invention. Such compounds are useful, forexample, as analytical tools, as probes in biological assays, or astherapeutic agents in accordance with the present invention.

3. Description of Exemplary Embodiments

In certain embodiments, the present invention provides inhibitors ofACC. In some embodiments, such compounds include those of formula I:

or a pharmaceutically acceptable salt thereof, wherein:

-   W is —C(O)—, —C(S)—, or —S(O)₂—;-   Q is —C(O)—, —C(S)—, —S(O)₂—, or N;-   X is —O—, —S—, —NR—, or N;-   Y is C or N;-   Z is C or N;-   R¹ is hydrogen or C₁₋₄ aliphatic, optionally substituted with one or    more halogens, —OR, —SR, —N(R)₂, —N(R)C(O)R, —C(O)N(R)₂,    —N(R)C(O)N(R)₂, —N(R)C(O)OR, —OC(O)N(R)₂, —N(R)SO₂R, —SO₂RN(R)₂,    —C(O)R, —C(O)OR, —OC(O)R, —C(O)OR, —S(O)R, or —SO₂R;-   R² is halogen, —R, —OR, —SR, —N(R)₂, —N(R)C(O)R, —C(O)N(R)₂,    —N(R)C(O)N(R)₂, —N(R)C(O)OR, —OC(O)N(R)₂, —N(R)SO₂R, —SO₂N(R)₂,    —C(O)R, —C(O)OR, —OC(O)R, —S(O)R, or —SO₂R, —B(OR)₂, or Hy, where Hy    is selected from 4-8 membered saturated or partially unsaturated    monocyclic heterocyclic ring having 1-2 heteroatoms independently    selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic    heteroaromatic ring having 1-4 heteroatoms independently selected    from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic    heteroaromatic ring having 1-5 heteroatoms independently selected    from nitrogen, oxygen, or sulfur; wherein R² is not optionally    substituted benzyl; or    -   R¹ and R² are taken together to form an optionally substituted        4-7 membered partially unsaturated carbocyclo-, or heterocyclo-,        benzo-, or 5-6 membered heteroarylo-fused ring;-   each R is independently hydrogen, deuterium, or an optionally    substituted group selected from C₁₋₆ aliphatic, a 3-8 membered    saturated or partially unsaturated monocyclic carbocyclic ring,    phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring; a 4-8    membered saturated or partially unsaturated monocyclic heterocyclic    ring having 1-2 heteroatoms independently selected from nitrogen,    oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring    having 1-4 heteroatoms independently selected from nitrogen, oxygen,    or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having    1-5 heteroatoms independently selected from nitrogen, oxygen, or    sulfur;-   L¹ is a covalent bond or a 1-6 membered straight or branched    bivalent hydrocarbon chain optionally substituted with R⁵ and    R^(5′);-   L² is a covalent bond or a 1-6 membered straight or branched    bivalent hydrocarbon chain optionally substituted with R⁷ and    R^(7′);-   R³ is halogen, —CN, —OR, —SR, —N(R)₂, —N(R)C(O)R, —C(O)RN(R)₂,    —C(O)N(R)S(O)₂R, —N(R)C(O)N(R)₂, —N(R)C(O)OR, —OC(O)N(R)₂,    —N(R)SO₂R, —SO₂N(R)₂, —C(O)R, —C(O)OR, —OC(O)R, —S(O)R, —SO₂R,    —B(OR)₂, or an optionally substituted ring selected from phenyl or    5-6 membered heteroaryl having 1-4 heteroatoms independently    selected from nitrogen, oxygen, or sulfur;-   R⁴ is hydrogen or a ring selected from a 3-8 membered monocyclic    saturated or partially unsaturated carbocyclic ring, a 4-8 membered    monocyclic saturated or partially unsaturated heterocyclic ring    having 1-2 heteroatoms independently selected from nitrogen, oxygen,    or sulfur, phenyl, an 8-10 membered bicyclic aryl ring, a 5-6    membered monocyclic heteroaryl ring having 1-4 heteroatoms    independently selected from nitrogen, oxygen, or sulfur, or an 8-10    membered bicyclic heteroaryl ring having 1-4 heteroatoms    independently selected from nitrogen, oxygen, or sulfur; wherein    said ring is optionally substituted with n instances of R⁸;-   each of R⁵ and R⁵′ is independently —R, —OR, —SR, —N(R)₂,    —N(R)C(O)R, —C(O)N(R)₂, —N(R)C(O)N(R)₂, —N(R)C(O)OR, —OC(O)N(R)₂,    —N(R)SO₂R, —SO₂N(R)₂, —C(O)R, —C(O)OR, —OC(O)R, —S(O)R, or —SO₂R; or    R⁵ and R^(5′) are taken together to form a cyclopropylenyl,    cyclobutylenyl, or oxetanyl group;-   each of R⁷ and R^(7′) is independently, —R, —OR⁶, —SR, —N(R)₂,    —N(R)C(O)R, —C(O)N(R)₂, —N(R)C(O)N(R)₂, —N(R)C(O)OR, —OC(O)N(R)₂,    —N(R)SO₂R, —SO₂N(R)₂, —C(O)R, —C(O)OR, —OC(O)R, —S(O)R, —SO₂R, or    —B(OR)₂; or R⁷ and R^(7′) are taken together to form a 3-8 membered    saturated or partially unsaturated monocyclic carbocyclic ring, or a    4-8 membered saturated or partially unsaturated monocyclic    heterocyclic ring having 1-2 heteroatoms independently selected from    nitrogen, oxygen, or sulfur;-   R⁶ is —R, —C(O)N(R)₂, or —C(O)R;-   each R⁸ is independently selected from halogen, —R, —OR, —SR, —N(R)₂    or deuterium; and-   n is 0-5.

In certain embodiments, if L² is a covalent bond, then R⁴ is nothydrogen. In certain embodiments, the group -L²-R⁴ is not alkyl when R²is unsubstituted alkyl. In certain embodiments, the group -L¹-R³ takentogether is not unsubstituted alkyl. In certain embodiments, R¹ is notthe group —CH₂C(O)N(R)V, where V is an aryl or heteroaryl ring, when-L¹-R³ taken together is unsubstituted alkyl.

As defined generally above, W is —C(O)—, —C(S)—, or —S(O)₂—. In someembodiments W is —C(O)—. In some embodiments, W is —C(S)—. In someembodiments, W is —S(O)₂—. In some embodiments, when W is —S(O)₂—, thenQ is not also —S(O)₂—.

As defined generally above, Q is —C(O)—, —C(S)—, —S(O)₂—, or N. In someembodiments, Q is —C(O)—. In some embodiments, Q is —C(S)—. In someembodiments, Q is —S(O)₂—. In some embodiments, Q is N.

As defined generally above, X is —O—, —S—, —NR— or N. In certainembodiments, X is —O—. In certain embodiments, X is —S—. In someembodiments, X is —NR—. In some embodiments, X is —NH—. In someembodiments, X is N.

As defined generally above, Y is C or N. In some embodiments Y is C. Insome embodiments, Y is N.

As defined generally above, Z is C or N. In some embodiments Z is C. Insome embodiments, Z is N.

In some embodiments, Z is not N when both W and Q are —C(O)—. In someembodiments, Z is not N when both W and Q are —C(O)— and Y is C.

As defined generally above, R¹ is hydrogen or C₁₋₄ aliphatic, optionallysubstituted with one or more halogens, —OR, —SR, —N(R)₂, —N(R)C(O)R,—C(O)N(R)₂, —N(R)C(O)N(R)₂, —N(R)C(O)OR, —OC(O)N(R)₂, —N(R)SO₂R,—SO₂N(R)₂, —C(O)R, —C(O)OR, —OC(O)R, —S(O)R, or —SO₂R. In certainembodiments, R¹ is hydrogen. In some embodiments, R¹ is C₁₋₄ aliphatic.In some embodiments, R¹ is methyl. In some embodiments, R¹ istrifluoromethyl.

As defined generally above, R² is halogen, —R, —OR, —SR, —N(R)₂,—N(R)C(O)R, —C(O)N(R)₂, —N(R)C(O)N(R)₂, —N(R)C(O)OR, —OC(O)N(R)₂,—N(R)SO₂R, —SO₂N(R)₂, —C(O)R, —C(O)OR, —OC(O)R, —S(O)R, —SO₂R, —B(OR)₂,or Hy. In certain embodiments, R² is halogen. In certain embodiments, R²is methyl. In certain embodiments, R² is trifluoromethyl. In certainembodiments, R² is fluorine. In certain embodiments, R² is chlorine. Incertain embodiments, R² is bromine. In certain embodiments, R² isiodine. In certain embodiments, R² is —C(O)OR or —C(O)N(R)₂. In someembodiments, R² is Hy. In some embodiments, R² is a 3-8 memberedsaturated or partially unsaturated monocyclic carbocyclic ring. In someembodiments, R² is cyclobutyl.

As defined generally above, Hy is selected from 4-8 membered saturatedor partially unsaturated monocyclic heterocyclic ring having 1-2heteroatoms independently selected from nitrogen, oxygen, or sulfur, a5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or an 8-10membered bicyclic heteroaromatic ring having 1-5 heteroatomsindependently selected from nitrogen, oxygen, or sulfur. In someembodiments, Hy is a 4-8 membered saturated or partially unsaturatedmonocyclic heterocyclic ring having 1-2 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur. In some embodiments, Hy is a5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur. In someembodiments, Hy is an 8-10 membered bicyclic heteroaromatic ring having1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.In some embodiments, Hy is oxazolyl. In some embodiments, Hy isthiazolyl. In some embodiments, Hy is triazolyl.

In some embodiments, R¹ and R² are taken together to form an optionallysubstituted 4-7 membered partially unsaturated carbocyclic ring. In someembodiments, R¹ and R² are taken together to form an optionallysubstituted 4-7 membered partially unsaturated carbocyclo-, orheterocyclo-, benzo-, or 5-6 membered heteroarylo-fused ring;

As defined generally above, R³ is halogen, —CN, —OR, —SR, —N(R)₂,—N(R)C(O)R, —C(O)N(R)₂, —C(O)N(R)S(O)₂R, —N(R)C(O)N(R)₂, —N(R)C(O)OR,—OC(O)N(R)₂, —N(R)SO₂R, —SO₂N(R)₂, —C(O)R, —C(O)OR, —OC(O)R, —S(O)R,—SO₂R, —B(OR)₂, or an optionally substituted ring selected from phenyl,and a 5-6 membered heterocyclyl or heteroaryl having 1-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur. In certainembodiments, R³ is —CN, —OR, —C(O)OR, —C(O)N(R)₂, —SO₂R, or anoptionally substituted ring selected from phenyl and a 5-6 memberedheterocyclyl or heteroaryl having 1-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur. In some embodiments, R³ is —OR. Insome embodiments, R³ is —C(O)OR. In some embodiments, R³ is phenyl ortetrazolyl. In some embodiments, R³ is isothiazolidine-1,1-dioxide. Insome embodiments, R³ is pyrrolidinylcarbonyl.

As defined generally above, each R is independently hydrogen or anoptionally substituted group selected from C₁₋₆ aliphatic, a 3-8membered saturated or partially unsaturated monocyclic carbocyclic ring,phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring; a 4-8membered saturated or partially unsaturated monocyclic heterocyclic ringhaving 1-2 heteroatoms independently selected from nitrogen, oxygen, orsulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4heteroatoms independently selected from nitrogen, oxygen, or sulfur, oran 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatomsindependently selected from nitrogen, oxygen, or sulfur.

In certain embodiments, each R is independently hydrogen or anoptionally substituted group selected from C₁₋₆ aliphatic, 3-8 memberedunsaturated or partially unsaturated monocyclic carbocyclic ring. Insome embodiments, each R is independently hydrogen or optionallysubstituted C₁₋₆ aliphatic.

As defined generally above, L¹ is a covalent bond or a 1-6 memberedstraight or branched bivalent hydrocarbon chain optionally substitutedwith R⁵ and R^(5′), or a cyclopropylenyl, cyclobutylenyl, or oxetanylgroup. In certain embodiments, L¹ is a C₁₋₃ straight or branchedbivalent hydrocarbon chain optionally substituted with R⁵ and R^(5′). Insome embodiments, L¹ is a straight or branched bivalent C₂ hydrocarbonchain. In some embodiments L¹ is a straight or branched bivalent C₃hydrocarbon chain. In certain embodiments, L¹ is a C₁ bivalenthydrocarbon chain substituted with R⁵ and R^(5′). In some embodiments,L¹ is a cyclopropylenyl, cyclobutylenyl, or oxetanyl group.

As defined generally above, In some embodiments, L² is a covalent bondor a 1-6 membered straight or branched bivalent hydrocarbon chainoptionally substituted with R⁷ and R^(7′). optionally substituted C₁-3straight or branched hydrocarbon chain. In some embodiments L² is anoptionally substituted C₂ straight hydrocarbon chain. In someembodiments L² is an optionally substituted C₃ straight or branchedhydrocarbon chain.

In some embodiments, L² is an optionally substituted C₁₋₃ straight orbranched hydrocarbon chain. In some embodiments L² is an optionallysubstituted C₂ straight hydrocarbon chain. In some embodiments L² is anoptionally substituted C₃ straight or branched hydrocarbon chain.

As defined generally above, R⁴ is hydrogen or a ring selected from a 3-8membered monocyclic saturated or partially unsaturated carbocyclic ring,a 4-8 membered monocyclic saturated or partially unsaturatedheterocyclic ring having 1-2 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, phenyl, an 8-10 membered bicyclic arylring, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or an 8-10membered bicyclic heteroaryl ring having 1-4 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur; wherein said ring isoptionally substituted with n instances of R⁸.

In certain embodiments, R⁴ is hydrogen. In some embodiments, R⁴ is a 5-6membered monocyclic saturated or partially unsaturated ring; whereinsaid ring is optionally substituted with n instances of R⁸. In someembodiments R⁴ is a 5-6 membered monocyclic saturated or partiallyunsaturated heterocyclic ring having 1-2 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur; wherein said ring isoptionally substituted with n instances of R⁸. In some embodiments, R⁴is phenyl; wherein said ring is optionally substituted with n instancesof R⁸. In some embodiments R⁴ is an 10 membered bicyclic aryl ring;wherein said ring is optionally substituted with n instances of R⁸. Insome embodiments, R⁴ is an 5-6 membered monocyclic heteroaryl ringhaving 1-4 heteroatoms independently selected from nitrogen, oxygen, orsulfur; wherein said ring is optionally substituted with n instances ofR⁸. In some embodiments, R⁴ is an 8-10 membered bicyclic heteroaryl ringhaving 1-4 heteroatoms independently selected from nitrogen, oxygen, orsulfur; wherein said ring is optionally substituted with n instances ofR⁸.

As defined generally above, each of R⁵ and R⁵′ is independently —R, —OR,—SR, —N(R)₂, —N(R)C(O)R, —C(O)N(R)₂, —N(R)C(O)N(R)₂, —N(R)C(O)OR,—OC(O)N(R)₂, —N(R)SO₂R, —SO₂N(R)₂, —C(O)R, —C(O)OR, —OC(O)R, —S(O)R, or—SO₂R; or R⁵ and R^(5′) are taken together to form a cyclopropylenyl,cyclobutylenyl, or oxetanyl group.

In some embodiments, each of R⁵ and R^(5′) is —R, wherein —R is nothydrogen. In some embodiments, each of R⁵ and R⁵′ is methyl. In someembodiments, R⁵ and R^(5′) are taken together to form a cyclopropylenyl,cyclobutylenyl, or oxetanyl group. In some embodiments, R⁵ and R^(5′)are taken together to form a cyclobutylenyl group.

As defined generally above, each of R⁷ and R^(7′) is independentlyhydrogen, —R, —OR⁶, —SR, —N(R)₂, —N(R)C(O)R, —C(O)N(R)₂, —N(R)C(O)N(R)₂,—N(R)C(O)O R, —OC(O)N(R)₂, —N(R)SO₂R, —SO₂N(R)₂, —C(O)R, —C(O)OR,—OC(O)R, —S(O)R, —SO₂R, or —B(OR)₂; or R⁷ and R^(7′) are taken togetherto form a 3-8 membered saturated or partially unsaturated monocycliccarbocyclic ring, or a 4-8 membered saturated or partially unsaturatedmonocyclic heterocyclic ring having 1-2 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur.

In certain embodiments, one of R⁷ and R^(7′) is hydrogen, and the otheris —OR⁶. In some embodiments one of R⁷ and R^(7′) is hydrogen, and theother is isopropoxy. In some embodiments R⁷ and R^(7′) are takentogether to form a 3-6 membered saturated or partially unsaturatedmonocyclic carbocyclic ring. In some embodiments R⁷ and R^(7′) are takentogether to form a 4-6 membered saturated or partially unsaturatedmonocyclic heterocyclic ring having 1-2 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur. In some embodiments, one ofR⁷ and R^(7′) is hydrogen and the other is —OR⁶.

As described generally above, R⁶ is —R, —C(O)N(R)₂, or —C(O)R. Incertain embodiments R⁶ is —R. In certain embodiments, R⁶ is hydrogen. Incertain embodiments, R⁶ is isopropyl. In certain embodiments R⁶ istetrahydropyranyl. In certain embodiments R⁶ is tetrahydrofuranyl. Incertain embodiments, R⁶ is tetrahydro-2H-thiopyran-1,1-dioxide. Incertain embodiments, R⁶ is 4-hydroxycyclohexyl.

As defined generally above, each R⁸ is independently selected fromhalogen, —R, —OR, —SR, —N(R)₂ or deuterium. In certain embodiments, eachR⁸ is independently selected from halogen, —R, and —OR. In certainembodiments, each R⁸ is halogen. In certain embodiments, R⁸ is —OR. Incertain embodiments, R⁸ is methoxy.

As defined generally above, n is 0-5. In certain embodiments, n is 0. Insome embodiments, n is 1-2. In some embodiments, n is 1. In someembodiments, n is 5.

In some embodiments, the present invention provides a compound offormula I selected from formulas I-a, I-b, I-c, I-d, I-e, I-f, I-g, andI-h:

or a pharmaceutically acceptable salt thereof; wherein each of R¹, R²,R³, R⁴, L¹, and L² is as described in embodiments for formula I, supra,or described in embodiments herein, both singly and in combination.

In certain embodiments, the present invention provides a compound offormula II:

or a pharmaceutically acceptable salt thereof, wherein:

-   each of Q, W, X, Y, Z, R¹, R², R³, R⁴, R⁵, R^(5′), R⁷, and R^(7′) is    as described in embodiments for formula I, supra, or described in    embodiments herein, both singly and in combination.

In certain embodiments, the present invention provides a compound offormula II selected from formulas II-a, II-b, II-c, II-d, II-e, II-f,II-g, and II-h:

or a pharmaceutically acceptable salt thereof; wherein each variable isas described in embodiments for formula II, supra, or described inembodiments herein, both singly and in combination.

In certain embodiments, the present invention provides a compound offormula III:

or a pharmaceutically acceptable salt thereof, wherein:

-   each of Q, W, X, Y, Z, R, R¹, R², R³, R⁵, R^(5′), R⁶, R⁸, and n is    as described in embodiments for formulas I and II, supra, or    described in embodiments herein, both singly and in combination.

In certain embodiments, the present invention provides a compound offormula III selected from formulas III-a, III-b, III-c, III-d, III-e,III-f, III-g, and III-h:

or a pharmaceutically acceptable salt thereof; wherein each variable isas described in embodiments for formula III, supra, or described inembodiments herein, both singly and in combination.

In certain embodiments, the present invention provides a compound offormula IV:

or a pharmaceutically acceptable salt thereof, wherein:

-   each of W, X, Y, Z, R, R¹, R², R³, R⁵, R^(5′), R⁶, R⁸, and n is as    described in embodiments for formulas I, II, and III, supra, or    described in embodiments herein, both singly and in combination.

In certain embodiments, the present invention provides a compound offormula IV selected from formulas IV-a, IV-b, IV-c, IV-d, IV-e, IV-f,and IV-g:

or a pharmaceutically acceptable salt thereof; wherein each variable isas described in embodiments for formulas I, II, and III, supra, ordescribed in embodiments herein, both singly and in combination.

In certain embodiments, the present invention provides a compound offormula V-i or V-ii:

or a pharmaceutically acceptable salt thereof, wherein Q, W, X, Y, Z,R², R³, R⁵, R^(5′), are as described in embodiments for formula I,supra; and

R¹ is H, D, CH₃ or CD₃;

each of R⁵ and R⁵′ is independently CH₃ or CD₃

R⁹ is CH(CH₃)₂, CH(CD₃)₂, CD(CH₃)₂, CD(CD₃)₂, or a group of formula:

wherein each X¹ is independently H or D;

each instance of X², Y¹, Z¹, and Z² is independently H or D; and

R¹⁰ is CH₃, CD₃, CH₂CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂, CF₂H, CH₂CD₃, CD₂CH₃, orCD₂CD₃.

In some embodiments, the compound of formula V-i or V-ii contains atleast one deuterium atom. In some embodiments, the compound of formulaV-i or V-ii contains at least two deuterium atoms. In some embodiments,the compound of formula V-i or V-ii contains at least three deuteriumatoms.

In some embodiments, the present invention provides a compound offormula V-i or V-ii wherein R² is selected from bromine, —C(O)OCD₂CD₃,—C(O)OCD₂CH₃, —C(O)OCH₂CD₃ and

In certain embodiments, the present invention provides a compound offormula I, wherein R² is Hy, thereby forming a compound of formula VI:

or a pharmaceutically acceptable salt thereof, wherein each of Q, W, X,Y, Z, L¹, L², R¹, R³, R⁴, and Hy is defined above and described inembodiments herein, both singly and in combination.

In certain embodiments, the present invention provides a compound offormula I, wherein R² is —C(O)OR, thereby forming a compound of formulaVII:

or a pharmaceutically acceptable salt thereof, wherein each of Q, W, X,Y, Z, L¹, L², R, R¹, R³, and R⁴ is defined above and described inembodiments herein, both singly and in combination.

In certain embodiments, the present invention provides a compound offormula II, wherein R² is Hy, thereby forming a compound of formulaVIII:

or a pharmaceutically acceptable salt thereof, wherein each of Q, W, X,Y, Z, R¹, R³, R⁴, R⁵, R^(5′), R⁷, R^(7′), and Hy is defined above anddescribed in embodiments herein, both singly and in combination.

In certain embodiments, the present invention provides a compound offormula II, wherein R² is —C(O)OR, thereby forming a compound of formulaIX:

or a pharmaceutically acceptable salt thereof, wherein each of R, Q, W,X, Y, Z, R¹, R³, R⁴, R⁵, R^(5′), R⁷, R^(7′) is defined above anddescribed in embodiments herein, both singly and in combination.

Exemplary compounds of formula I are set forth in Table 1, below:

TABLE 1 Exemplary Compounds of Formula I Cmpd # Compound Structure I-1 

I-2 

I-3 

I-4 

I-5 

I-6 

I-7 

I-8 

I-9 

I-10

I-11

I-12

I-13

I-14

I-15

I-16

I-17

I-18

I-19

I-20

I-21

I-22

I-23

I-24

I-25

I-26

I-27

I-28

I-29

I-30

I-31

I-32

I-33

I-34

I-35

I-36

I-37

I-38

I-39

I-40

I-41

I-42

I-43

I-44

I-45

I-46

I-47

I-48

I-49

In certain embodiments, the present invention provides any compoundselected from those depicted in Table 1, above, or a pharmaceuticallyacceptable salt thereof.

4. Uses, Formulation and Administration and Pharmaceutically AcceptableCompositions

According to another embodiment, the invention provides a compositioncomprising a compound of this invention or a pharmaceutically acceptablesalt, ester, or salt of ester thereof and a pharmaceutically acceptablecarrier, adjuvant, or vehicle. The amount of compound in compositions ofthis invention is such that is effective to measurably inhibit ACC, in abiological sample or in a patient. In certain embodiments, the amount ofcompound in compositions of this invention is such that is effective tomeasurably inhibit ACC, in a biological sample or in a patient. Incertain embodiments, a composition of this invention is formulated foradministration to a patient in need of such composition. In someembodiments, a composition of this invention is formulated for oraladministration to a patient.

The term “patient,” as used herein, means an animal, preferably amammal, and most preferably a human.

The term “pharmaceutically acceptable carrier, adjuvant, or vehicle”refers to a non-toxic carrier, adjuvant, or vehicle that does notdestroy the pharmacological activity of the compound with which it isformulated. Pharmaceutically acceptable carriers, adjuvants or vehiclesthat may be used in the compositions of this invention include, but arenot limited to, ion exchangers, alumina, aluminum stearate, lecithin,serum proteins, such as human serum albumin, buffer substances such asphosphates, glycine, sorbic acid, potassium sorbate, partial glyceridemixtures of saturated vegetable fatty acids, water, salts orelectrolytes, such as protamine sulfate, disodium hydrogen phosphate,potassium hydrogen phosphate, sodium chloride, zinc salts, colloidalsilica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-basedsubstances, polyethylene glycol, sodium carboxymethylcellulose,polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers,polyethylene glycol and wool fat.

A “pharmaceutically acceptable derivative” means any non-toxic salt,ester, salt of an ester or other derivative of a compound of thisinvention that, upon administration to a recipient, is capable ofproviding, either directly or indirectly, a compound of this inventionor an inhibitorily active metabolite or residue thereof.

As used herein, the term “inhibitorily active metabolite or residuethereof” means that a metabolite or residue thereof is also an inhibitorof ACC.

Compositions of the present invention may be administered orally,parenterally, by inhalation spray, topically, rectally, nasally,buccally, vaginally or via an implanted reservoir. The term “parenteral”as used herein includes subcutaneous, intravenous, intramuscular,intra-articular, intra-synovial, intrasternal, intrathecal,intrahepatic, intralesional and intracranial injection or infusiontechniques. Preferably, the compositions are administered orally,intraperitoneally or intravenously. Sterile injectable forms of thecompositions of this invention may be aqueous or oleaginous suspension.These suspensions may be formulated according to techniques known in theart using suitable dispersing or wetting agents and suspending agents.The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally acceptable diluent orsolvent, for example as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium.

For this purpose, any bland fixed oil may be employed includingsynthetic mono- or di-glycerides. Fatty acids, such as oleic acid andits glyceride derivatives are useful in the preparation of injectables,as are natural pharmaceutically-acceptable oils, such as olive oil orcastor oil, especially in their polyoxyethylated versions. These oilsolutions or suspensions may also contain a long-chain alcohol diluentor dispersant, such as carboxymethyl cellulose or similar dispersingagents that are commonly used in the formulation of pharmaceuticallyacceptable dosage forms including emulsions and suspensions. Othercommonly used surfactants, such as Tweens, Spans and other emulsifyingagents or bioavailability enhancers which are commonly used in themanufacture of pharmaceutically acceptable solid, liquid, or otherdosage forms may also be used for the purposes of formulation.

Pharmaceutically acceptable compositions of this invention may be orallyadministered in any orally acceptable dosage form including, but notlimited to, capsules, tablets, aqueous suspensions or solutions. In thecase of tablets for oral use, carriers commonly used include lactose andcorn starch. Lubricating agents, such as magnesium stearate, are alsotypically added. For oral administration in a capsule form, usefuldiluents include lactose and dried cornstarch. When aqueous suspensionsare required for oral use, the active ingredient is combined withemulsifying and suspending agents. If desired, certain sweetening,flavoring or coloring agents may also be added.

Alternatively, pharmaceutically acceptable compositions of thisinvention may be administered in the form of suppositories for rectaladministration. These can be prepared by mixing the agent with asuitable non-irritating excipient that is solid at room temperature butliquid at rectal temperature and therefore will melt in the rectum torelease the drug. Such materials include cocoa butter, beeswax andpolyethylene glycols.

Pharmaceutically acceptable compositions of this invention may also beadministered topically, especially when the target of treatment includesareas or organs readily accessible by topical application, includingdiseases of the eye, the skin, or the lower intestinal tract. Suitabletopical formulations are readily prepared for each of these areas ororgans.

Topical application for the lower intestinal tract can be effected in arectal suppository formulation (see above) or in a suitable enemaformulation. Topically-transdermal patches may also be used.

For topical applications, provided pharmaceutically acceptablecompositions may be formulated in a suitable ointment containing theactive component suspended or dissolved in one or more carriers.Carriers for topical administration of compounds of this inventioninclude, but are not limited to, mineral oil, liquid petrolatum, whitepetrolatum, propylene glycol, polyoxyethylene, polyoxypropylenecompound, emulsifying wax and water. Alternatively, providedpharmaceutically acceptable compositions can be formulated in a suitablelotion or cream containing the active components suspended or dissolvedin one or more pharmaceutically acceptable carriers. Suitable carriersinclude, but are not limited to, mineral oil, sorbitan monostearate,polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol,benzyl alcohol and water.

For ophthalmic use, provided pharmaceutically acceptable compositionsmay be formulated as micronized suspensions in isotonic, pH adjustedsterile saline, or, preferably, as solutions in isotonic, pH adjustedsterile saline, either with or without a preservative such asbenzylalkonium chloride. Alternatively, for ophthalmic uses, thepharmaceutically acceptable compositions may be formulated in anointment such as petrolatum.

Pharmaceutically acceptable compositions of this invention may also beadministered by nasal aerosol or inhalation. Such compositions areprepared according to techniques well-known in the art of pharmaceuticalformulation and may be prepared as solutions in saline, employing benzylalcohol or other suitable preservatives, absorption promoters to enhancebioavailability, fluorocarbons, and/or other conventional solubilizingor dispersing agents.

Most preferably, pharmaceutically acceptable compositions of thisinvention are formulated for oral administration. Such formulations maybe administered with or without food. In some embodiments,pharmaceutically acceptable compositions of this invention areadministered without food. In other embodiments, pharmaceuticallyacceptable compositions of this invention are administered with food.

The amount of compounds of the present invention that may be combinedwith the carrier materials to produce a composition in a single dosageform will vary depending upon the host treated, the particular mode ofadministration. Preferably, provided compositions should be formulatedso that a dosage of between 0.01-100 mg/kg body weight/day of theinhibitor can be administered to a patient receiving these compositions.

It should also be understood that a specific dosage and treatmentregimen for any particular patient will depend upon a variety offactors, including the activity of the specific compound employed, theage, body weight, general health, sex, diet, time of administration,rate of excretion, drug combination, and the judgment of the treatingphysician and the severity of the particular disease being treated. Theamount of a compound of the present invention in the composition willalso depend upon the particular compound in the composition.

Uses of Compounds and Pharmaceutically Acceptable Compositions

Acetyl-CoA carboxylase (ACC) catalyzes the ATP-dependent carboxylationof acetyl-CoA to form malonyl-CoA. This reaction, which proceeds in twohalf-reactions, a biotin carboxylase (BC) reaction and acarboxyltransferase (CT) reaction, is the first committed step in fattyacid (FA) biosynthesis and is the rate-limiting reaction for thepathway. In addition to its role as a substrate in FA biosynthesis,malonyl-CoA, the product of the ACC-catalyzed reaction, also plays animportant regulatory role in controlling mitochondrial FA uptake throughallosteric inhibition of carnitine palmitoyltransferase I (CPT-I), theenzyme catalyzing the first committed step in mitochondrial FAoxidation. Malonyl-CoA, therefore, is a key metabolic signal for thecontrol of FA production and utilization in response to dietary changesand altered nutritional requirements in animals, for example duringexercise, and therefore plays a key role in controlling the switchbetween carbohydrate and fat utilization in liver and skeletal muscle[Harwood, 2005].

In mammals, ACC exists as two tissue-specific isozymes, ACC1 which ispresent in lipogenic tissues (liver, adipose) and ACC2, which is presentin oxidative tissues (liver, heart, skeletal muscle). ACC1 and ACC2 areencoded by separate genes, display distinct cellular distributions, andshare 75% overall amino acid sequence identity, except for an extensionat the N-terminus of ACC2 that direct ACC2 to the mitochondrialmembrane. ACC1, which lacks this targeting sequence, is localized to thecytoplasm. In the heart and skeletal muscle, which have a limitedcapacity to synthesize fatty acids, the malonyl-CoA formed by ACC2functions to regulate FA oxidation. In the liver, the malonyl-CoA formedin the cytoplasm through the actions of ACC1 is utilized for FAsynthesis and elongation leading to triglyceride formation and VLDLproduction, whereas the malonyl-CoA formed at the mitochondrial surfaceby ACC2 acts to regulate FA oxidation [Tong and Harwood, J. CellularBiochem. 99: 1476, 2006]. This compartmentalization of malonyl-CoAresults from a combination of synthesis proximity [Abu-Elheiga et al.,PNAS (USA) 102: 12011, 2005] and the rapid action of malonyl-CoAdecarboxylase [Cheng et al., J. Med. Chem. 49:1517, 2006].

Simultaneous inhibition of the enzymatic activities of ACC1 and ACC2offers the ability to inhibit de novo FA production in lipogenic tissues(e.g. liver & adipose) while at the same time stimulating FA oxidationin oxidative tissues (e.g. liver & skeletal muscle) and therefore offersan attractive modality for favorably affecting, in a concerted manner, amultitude of cardiovascular risk factors associated with obesity,diabetes, insulin resistance, and the metabolic syndrome.

Several lines of evidence strongly support the concept of directinhibition of ACC activity as an important therapeutic target fortreating obesity, diabetes, insulin resistance, and the metabolicsyndrome.

Abu-Elheiga et al. [Proc. Natl. Acad. Sci. USA 100:10207-10212, 2003]demonstrated that ACC2 knock-out mice exhibit reduced skeletal andcardiac muscle malonyl-CoA, increased muscle FA oxidation, reducedhepatic fat, reduced total body fat, elevated skeletal muscle uncouplingprotein-3 (UCP3) which is indicative of increased energy expenditure,reduced body weight, reduced plasma free FAs, reduced plasma glucose,and reduced tissue glycogen, and are protected from diet-induceddiabetes and obesity.

Savage et al. [J. Clin. Invest. 116: 817, 2006], using ACC1 and ACC2antisense oligonucleotides, demonstrated stimulation of FA oxidation inisolated rat hepatocytes and in rats fed high-fat diets, and lowering ofhepatic triglycerides, improvements in insulin sensitivity, reductionsin hepatic glucose production, and increases in UCP1 mRNA in highfat-fed rats. These effects were greater when both ACC1 and ACC2expression were suppressed than when either ACC1 or ACC2 expressionalone was suppressed.

Harwood et al. [J. Biol. Chem. 278: 37099, 2003] demonstrated that theisozyme-nonselective ACC inhibitor, CP-640186, which equally inhibitsACC1 and ACC2 (IC₅₀=˜60 nM) isolated from rat, mouse, monkey and humanwithout inhibiting either pyruvate carboxylase or propionyl-CoAcarboxylase, reduced FA synthesis, triglyceride synthesis and secretionin Hep-G2 cells without affecting cholesterol synthesis, and reducedapoB secretion without affecting apoA1 secretion. CP-640186 alsostimulated FA oxidation in C2C12 cells and in rat muscle slices andincreased CPT-I activity in Hep-G2 cells. In experimental animals,CP-640186 acutely reduced malonyl-CoA concentration in both lipogenicand oxidative tissues in both the fed and fasted state, reduced liverand adipose tissue FA synthesis, and increased whole body FA oxidation.In sucrose-fed rats treated with CP-640186 for three weeks, CP-640186time- and dose-dependently reduced liver, muscle and adiposetriglycerides, reduced body weight due to selective fat reductionwithout reducing lean body mass, reduced leptin levels, reduced thehyperinsulinemia produced by the high sucrose diet without changingplasma glucose levels, and improved insulin sensitivity.

Saha et al. [Diabetes 55:A288, 2006] demonstrated stimulation of insulinsensitivity in insulin-resistant rat muscle tissue by CP-640186 within30 min of compound administration, and studies by Furler et al.[Diabetes 55:A333, 2006] used dual tracer analysis to show that acute(46 min) treatment of rats with CP-640186 stimulated FA clearancewithout decreasing glucose clearance.

ACC is the rate-limiting enzyme in fatty acid synthesis and its product,malonyl CoA, serves as an important regulator of fatty acid oxidation.Hence, ACC inhibitors both reduce de novo lipid synthesis and promotethe oxidation of existing fat. This dual effect on lipid metabolismraises the possibility that ACC inhibitors will be substantially moreeffective in reducing excess fat than other mechanisms. Furthermore, ACCinhibitors will impact insulin sensitivity, plasma and tissuetriglycerides, and fasting plasma glucose as a consequence of whole-bodyand tissue-specific fat mass reduction without the need forpoly-pharmacy.

ACC inhibitors need only access the liver and muscle in the peripheralcompartment. Avoiding the CNS will address many of side effectsassociated with the late-stage obesity programs targeting CNS receptors.ACC inhibitors are also expected to have superior safety profiles toexisting metabolic disease agents. For example, it is unlikely that anACC inhibitor will precipitate life-threatening hypoglycemia as is oftenseen with insulin mimetics, insulin secretagogues, and insulindegradation inhibitors. Also, since ACC inhibitors will reducewhole-body fat mass, they will be superior to the glitazones thatincrease whole-body fat mass as part of their mechanism of action.

A peripherally acting agent that causes significant weight loss andimproves other metabolic endpoints fits well within the US FDA'srequirements for approval of a new obesity agent. However, if anapproval for obesity continues to be challenging in 5-7 years, ACCinhibitors could be approved for familial combined hyperlipidemia andnon-alcoholic steatohepatitis (NASH). There are currently no marketedACC inhibitors, so an isozyme-nonselective ACC inhibitor would representfirst-in-class therapy for treating obesity and metabolic syndrome.

The activity of a compound utilized in this invention as an inhibitor ofACC or treatment for obesity or metabolic syndrome, may be assayed invitro or in vivo. An in vivo assessment of the efficacy of the compoundsof the invention may be made using an animal model of obesity ormetabolic syndrome, e.g., a rodent or primate model. Cell-based assaysmay be performed using, e.g., a cell line isolated from a tissue thatexpresses ACC. Additionally, biochemical or mechanism-based assays,e.g., transcription assays using a purified protein, Northern blot,RT-PCR, etc., may be performed. In vitro assays include assays thatdetermine cell morphology, protein expression, and/or the cytotoxicity,enzyme inhibitory activity, and/or the subsequent functionalconsequences of treatment of cells with compounds of the invention.Alternate in vitro assays quantitate the ability of the inhibitor tobind to protein or nucleic acid molecules within the cell. Inhibitorbinding may be measured by radiolabelling the inhibitor prior tobinding, isolating the inhibitor/target molecule complex and determiningthe amount of radiolabel bound. Alternatively, inhibitor binding may bedetermined by running a competition experiment where new inhibitors areincubated with purified proteins or nucleic acids bound to knownradioligands. Detailed conditions for assaying a compound utilized inthis invention as an inhibitor of ACC are set forth in the Examplesbelow. The aforementioned assays are exemplary and not intended to limitthe scope of the invention. The skilled practitioner can appreciate thatmodifications can be made to conventional assays to develop equivalentassays that obtain the same result.

As used herein, the terms “treatment,” “treat,” and “treating” refer toreversing, alleviating, delaying the onset of, or inhibiting theprogress of a disease or disorder, or one or more symptoms thereof, asdescribed herein. In some embodiments, treatment may be administeredafter one or more symptoms have developed. In other embodiments,treatment may be administered in the absence of symptoms. For example,treatment may be administered to a susceptible individual prior to theonset of symptoms (e.g., in light of a history of symptoms and/or inlight of genetic or other susceptibility factors). Treatment may also becontinued after symptoms have resolved, for example to prevent or delaytheir recurrence.

The compounds and compositions, according to the method of the presentinvention, may be administered using any amount and any route ofadministration effective for treating or lessening the severity of ametabolic disorder or condition, cancer, a bacterial infection, a fungalinfection, a parasitic infection (e.g. malaria), an autoimmune disorder,a neurodegenerative or neurological disorder, schizophrenia, abone-related disorder, liver disease, or a cardiac disorder.

In some embodiments, the compounds and compositions, according to themethod of the present invention, may be administered using any amountand any route of administration effective for treating or lessening theseverity of a disease associated with ACC (Tong et al. “Acetyl-coenzymeA carboxylase: crucial metabolic enzyme and attractive target for drugdiscovery” Cell and Molecular Life Sciences (2005) 62, 1784-1803).

In some embodiments, the compounds and compositions, according to themethod of the present invention, may be administered using any amountand any route of administration effective for treating or lessening theseverity of a metabolic disorder, disease, or condition. In someembodiments, the metabolic disorder is obesity, metabolic syndrome,diabetes or diabetes-related disorders including Type 1 diabetes(insulin-dependent diabetes mellitus, IDDM) and Type 2 diabetes(non-insulin-dependent diabetes mellitus, NIDDM), impaired glucosetolerance, insulin resistance, hyperglycemia, diabetic complications,including, but not limited to atherosclerosis, coronary heart disease,stroke, peripheral vascular disease, nephropathy, hypertension,neuropathy and nephropathy; obesity comorbidities including but notlimited to metabolic syndrome, dyslipidemia, Type III dyslipidemia,hypertension, insulin resistance, diabetes (including Type 1 and Type 2diabetes), coronary artery disease, and heart failure. In someembodiments, the metabolic disorder, disease or condition isnon-alcoholic fatty liver disease or hepatic insulin resistance.

In some embodiments, the present invention provides a method of treatinga metabolic disorder, disease, or condition described herein, comprisingadministering a compound of the invention in conjunction with one ormore pharmaceutical agents. Suitable pharmaceutical agents that may beused in combination with the compounds of the present invention includeanti-obesity agents (including appetite suppressants), anti-diabeticagents, anti-hyperglycemic agents, lipid lowering agents, andanti-hypertensive agents.

Suitable lipid lowering agents that can be used in conjunction withcompounds of the present invention include but are not limited to, bileacid sequestrants, HMG-CoA reductase inhibitors, HMG-CoA synthaseinhibitors, cholesterol absorption inhibitors, acyl coenzymeA-cholesterol acyl transferase (ACAT) inhibitors, CETP inhibitors,squalene synthetase inhibitors, PPAR-alpha agonists, FXR receptormodulators, LXR receptor modulators, lipoprotein synthesis inhibitors,renin-angiotensin system inhibitors, PPAR-delta partial agonists, bileacid reabsorption inhibitors, PPAR-gamma agonists, triglyceridesynthesis inhibitors, microsomal triglyceride transport inhibitors,transcription modulators, squalene epoxidase inhibitors, low densitylipoprotein receptor inducers, platelet aggregation inhibitors, 5-LO orFLAP inhibitors, niacin, and niacin-bound chromium.

Suitable anti-hypertensive agents that can be used in conjunction withcompounds of the present invention include but are not limited todiuretics, beta-adrenergic blockers, calcium channel blockers,angiotensin converting enzyme (ACE) inhibitors, neutral endopeptidaseinhibitors, endothelin antagonists, vasodilators, angiotensin IIreceptor antagonists, alpha/beta adrenergic blockers, alpha 1 blockers,alpha 2 agonists, aldosterone inhibitors, mineralocorticoid receptorinhibitors, renin inhibitors, and angiopoietin 2 binding agents.

Suitable anti-diabetic agents that can be used in conjunction withcompounds of the present invention include but are not limited to otheracetyl-CoA carboxylase (ACC) inhibitors, DGAT-1 inhibitors, AZD7687,LCQ908, DGAT-2 inhibitors, monoacylglycerol O-acyltransferaseinhibitors, PDE-10 inhibitors, AMPK activators, sulfonylureas (e.g.acetohexamide, chlorpropamide, diabinese, glibenclamide, glipizide,glyburide, blimipiride, gliclazide, glipentide, gliquidone, glisolamide,tolazamide, tolbutamide), meglitinides, alpha-amylase inhibitors (e.g.tendamistat, treastatin, AL-3688), alpha-glucoside hydrolase inhibitors(e.g. acarbose), alpha-glucosidase inhibitors (e.g. adiposine,camiglibose, emiglitate, miglitol, voglibose, pradimicin-Q,sarbostatin), PPAR-gamma agonists (e.g. balaglitazone, ciglitazone,darglitazone, englitazone, isaglitazone, pioglitazone, rosiglitazone,troglitazone), PPAR-alpha/gamma agonists (e.g. CLX-0940, GW-1536,GW-1929, GW-2433, KRP-297, L-796449, LR-90, MK-0767, SB-219994),biguanides (e.g. metformin, buformin), GLP-1 modulators (exendin-3,exendin-4), liraglutide, albiglutide, exenatide (Byetta), taspoglutide,lixisenatide, dulaglutide, semaglutide, N,N-9924, TTP-054, PTP-1Binhibitors (trodusquemine, hyrtiosal extract), SIRT-1 inhibitors (e.g.resveratrol, GSK2245840, GSK184072), DPP-IV inhibitors (e.g.sitagliptin, vildagliptin, alogliptin, dutogliptin, linagliptin,saxagliptin), insulin secretagogues, fatty acid oxidation inhibitors, A2antagonists, JNK inhibitors, glucokinase activators (e.g. TTP-399,TTP-355, TTP-547, AZD1656, ARRY403, MK-0599, TAK-329, AZD5658, GKM-001),insulin, insulin mimetics, glycogen phosphorylase inhibitors (e.g.GSK1362885), VPAC2 receptor agonists, SGLT2 inhibitors (dapagliflozin,canagliflozin, BI-10733, tofogliflozin, ASP-1941, THR1474, TS-071,ISIS388626, LX4211), glucagon receptor modulators, GPR119 modulators(e.g. MBX-2982, GSK1292263, APD597, PSN821), FGF21 derivatives, TGR5(GPBAR1) receptor agonists (e.g. INT777), GPR40 agonists (e.g. TAK-875),GPR120 agonists, nicotinic acid receptor (HM74A) activators, SGLT1inhibitors (e.g. GSK1614235), carnitine palmitoyl transferase enzymeinhibitors, fructose 1,6-diphosphatase inhibitors, aldose reductaseinhibitors, mineralocorticoid receptor inhibitors, TORC2 inhibitors,CCR2 inhibitors, CCR5 inhibitors, PKC (e.g. PKC-alpha, PKC-beta,PKC-gamma) inhibitors, fatty acid synthetase inhibitors, serinepalmitoyl transferase inhibitors, GPR81 modulators, GPR39 modulators,GPR43 modulators, GPR41 modulators, GPR105 modulators, Kv1.3 inhibitors,retinol binding protein 4 inhibitors, glucocorticoid receptormodulators, somatostatin receptor (e.g. SSTR1, SSTR2, SSTR3, SSTR5)inhibitors, PDHK2 inhibitors, PDHK4 inhibitors, MAP4K4 inhibitors,IL1-beta modulators, and RXR-alpha modulators.

Suitable anti-obesity agents include but are not limited to,11-beta-hydroxysteroid dehydrogenase 1 inhibitors, stearoyl-CoAdesaturase (SCD-1) inhibitors, MCR-4 agonists, CCK-A agonists, monoaminereuptake inhibitors (e.g. sibutramine), sympathomimetic agents,beta-3-adrenergic receptor agonists, dopamine receptor agonists (e.g.bromocriptine), melanocyte-stimulating hormone and analogs thereof,5-HT_(2C) agonists (e.g. lorcaserin/Belviq), melanin concentratinghormone antagonists, leptin, leptin analogs, leptin agonists, galaninantagonists, lipase inhibitors (e.g. tetrahydrolipstatin/Orlistat),anorectic agents (e.g. bombesin agonists), NPY antagonists (e.g.velneperit), PYY₃₋₃₆ (and analogs thereof), BRS3 modulators, opioidreceptor mixed antagonists, thyromimetic agents, dehydroepiandrosterone,glucocorticoid agonists or antagonists, orexin antagonists, GLP-1agonists, ciliary neurotrophic factors (e.g. Axokine), humanagouti-related protein (AGRP) inhibitors, H3 antagonists or inverseagonists, neuromedin U agonists, MTP/ApoB inhibitors (e.g. gut-selectiveMTP inhibitors such as dirlotapide, JTT130, Usistapide, SLX4090), MetAp2inhibitors (e.g. ZGN-433), agents with mixed modulatory activity at twoor more of glucagon, GIP, and GLP1 receptors (e.g. MAR-701, ZP2929),norepinephrine reuptake inhibitors, opioid antagonists (e.g.naltrexone), CB1 receptor antagonists or inverse agonists, ghrelinagonists or antagonists, oxyntomodulin and analogs thereof, monoamineuptake inhibitors (e.g. tesofensine), and combination agents (e.g.buproprion plus zonisamide (Empatic), pramlintide plus metreleptin,buproprion plus naltrexone (Contrave), phentermine plus topiramate(Qsymia).

In some embodiments, the anti-obesity agents used in combination withcompounds of the invention are selected from gut-selective MTPinhibitors (e.g. dirlotapide, mitratapide, implitapide, R56918), CCK-Aagonists, 5-HT_(2C) agonists (e.g. lorcaserin/Belviq), MCR4 agonists,lipase inhibitors (e.g. Cetilistat), PYY₃₋₃₆ (including analogs andPEGylated analogs thereof), opioid antagonists (e.g. naltrexone), oleoylestrone, obinepitide, pramlintide, tesofensine, leptin, bromocriptine,orlistat, AOD-9604, and sibutramine.

In some embodiments, the compounds and compositions, according to themethod of the present invention, may be administered using any amountand any route of administration effective for treating or lessening theseverity of a LKB1 or Kras associated disease. In some embodiments, theLKB1 or Kras associated disease is selected from hepatocellularcarcinoma, LKB1 mutant cancers, LKB1 loss of heterozygosity (LOH) drivencancers, Kras mutant cancers, Peutz-Jeghers syndrome (PJS), Cowden'sdisease (CD), and tubeous sclerosis (TS) (Makowski et al. “Role of LKB1in Lung Cancer Development” British Journal of Cancer (2008) 99,683-688). In some embodiments, the LKB1 or Kras associated disease is aKras positive/LKB1 deficient lung tumor.

In some embodiments, the compounds and compositions, according to themethod of the present invention, may be administered using any amountand any route of administration effective for treating or lessening theseverity of a cancer, or inhibiting the growth of or inducing apoptosisin cancer cells (Wang et al. “Acetyl-CoA Carboxylase-alpha InhibitorTOFA Induces Human Cancer Cell Apoptosis” Biochem Biophys Res Commun.(2009) 385(3), 302-306; Chajes et al. “Acetyl-CoA Carboxylase alpha IsEssential to Breast Cancer Cell Survival” Cancer Res. (2006) 66,5287-5294; Beckers et al. “Chemical Inhibition of Acetyl-CoA CarboxylaseInduces Growth Arrest and Cytotoxicity Selectivity in Cancer Cells”Cancer Res. (2007) 8180-8187; Brusselmans et al. “RNAInterference-Mediated Silencing of the Acetyl-CoA-Carboxylase-alpha GeneInduces Growth Inhibition and Apoptosis of Prostate Cancer Cells” CancerRes. (2005) 65, 6719-6725; Brunet et al. “BRCA1 and Acetyl-CoACarboxylase: The Metabolic Syndrom of Breast Cancer” MolecularCarcinogenesis (2008) 47, 157-163; Cairns et al. “Regulation of CancerCell Metabolism” (2011) 11, 85-95; Chiaradonna et al. “From CancerMetabolism to New Biomarkers and Drug Targets” Biotechnology Advances(2012) 30, 30-51).

In some embodiments, the compounds and compositions, according to themethod of the present invention, may be administered using any amountand any route of administration effective for treating or lessening theseverity of a melanoma. In some embodiments, the melanoma is one bearingan activated MAPK pathway (Petti et al. “AMPK activators inhibit theproliferation of human melanomas bearing the activated MAPK pathway”Melanoma Research (2012) 22, 341-350).

Compounds of the present invention find special utility in triplenegative breast cancer, as the tumor suppressor protein BRCA1 binds andstabilizes the inactive form of ACC, thus upregulating de novo lipidsynthesis, resulting in cancer cell proliferation Brunet et al. “BRCA1and acetyl-CoA carboxylase: the metabolic syndrome of breast cancer”Mol. Carcinog. (2008) 47(2), 157-163.

In some embodiments, the compounds and compositions, according to themethod of the present invention, may be administered using any amountand any route of administration effective for treating or lessening theseverity of a liposarcoma. Liposarcomas have been shown to depend on denovo long-chain fatty acid synthesis for growth, and inhibition of ACCby soraphen A inhibited lipogenesis as well as tumor cell growth (Olsenet al. “Fatty acid synthesis is a therapeutic target in humanliposarcoma” International J. of Oncology (2010) 36, 1309-1314).

In some embodiments, the compounds and compositions, according to themethod of the present invention, may be administered using any amountand any route of administration effective for treating or lessening theseverity of a liver disease. In some embodiments, the liver disease isselected from hepatitis C, hepatocellular carcinoma, familial combinedhyperlipidemia and non-alcoholic steatohepatitis (NASH), liver cancer,cholangiocarcinoma, angiosarcoma, hemangiosarcoma, and progressivefamilial intrahepatic cholestasis.

In some embodiments, the compounds and compositions, according to themethod of the present invention, may be administered using any amountand any route of administration effective for treating or lessening theseverity of a bacterial infection or inhibiting the growth of bacteria.

In some embodiments, the compounds and compositions, according to themethod of the present invention, may be administered using any amountand any route of administration effective for treating or lessening theseverity of a fungal infection or inhibiting the growth of fungal cells(Shen et al. “A Mechanism for the Potent Inhibition of EukaryoticAcetyl-Coenzyme A Carboxylase by Soraphen A, a Macrocyclic PolyketideNatural Product” Molecular Cell (2004) 16, 881-891). In someembodiments, the fungal infection occurs in a human. In someembodiments, the fungal infection is a Candida infection.

In some embodiments, the compounds and compositions, according to themethod of the present invention, may be administered using any amountand any route of administration effective for treating or lessening theseverity of a bacterial infection (Tong, L. et al. J. Cell. Biochem.(2006) 99, 1476-1488).

In some embodiments, the compounds and compositions, according to themethod of the present invention, may be administered using any amountand any route of administration effective for treating or lessening theseverity of a viral infection (Munger et al. Nat. Biotechnol. (2008) 26,1179-1186). In some embodiments, the viral infection is Hepatitis C.

In some embodiments, the compounds and compositions, according to themethod of the present invention, may be administered using any amountand any route of administration effective for treating or lessening theseverity of a neurological disease (Henderson et al. Neurotherapeutics(2008) 5, 470-480; Costantini et al. Neurosci. (2008) 9 Suppl. 2:S16;Baranano et al. Curr. Treat. Opin. Neurol. (2008) 10, 410-419).

In some embodiments, the compounds and compositions, according to themethod of the present invention, may be administered using any amountand any route of administration effective for treating or lessening theseverity of a parasitic infection or inhibiting the growth of parasites(e.g. malaria and toxoplasma: Gornicki et al. “Apicoplast fatty acidbiosynthesis as a target for medical intervention in apicomplexanparasites” International Journal of Parasitology (2003) 33, 885-896;Zuther et al. “Growth of Toxoplasma gondii is inhibited byaryloxyphenoxypropionate herbicides targeting acetyl-CoA carboxylase”PNAS (1999) 96 (23) 13387-13392).

In some embodiments, the compounds and compositions, according to themethod of the present invention, may be administered using any amountand any route of administration effective for treating or lessening theseverity of a cardiac disorder. In some embodiments, the cardiacdisorder is cardiac hypertrophy. In some embodiments the cardiacdisorder is treated or its severity lessened by the cardioprotectivemechanism resulting from increased fatty acid oxidation via ACCinhibition (Kolwicz et al. “Cardiac-specific deletion of acetyl CoAcarboxylase 2 (ACC2) prevents metabolic remodeling duringpressure-overload hypertrophy” Circ. Res. (2012); DOI:10.1161/CIRCRESAHA.112.268128).

In certain embodiments, the compounds and compositions, according to themethod of the present invention, may be used as herbicides. In someembodiments, the present invention provides a method to inhibit thegrowth or viability of plants comprising treating plants with compoundsof the present invention. In some embodiments of the present invention,compounds of the present invention can be used to inhibit the growth orviability of plants by inhibiting ACC. In some embodiments, the methodof the present invention comprises using compounds of the presentinvention to inhibit fatty acid production in or increase fatty acidoxidation in plants.

The exact amount required will vary from subject to subject, dependingon the species, age, and general condition of the subject, the severityof the infection, the particular agent, its mode of administration, andthe like. The compounds of the invention are preferably formulated indosage unit form for ease of administration and uniformity of dosage.The expression “dosage unit form” as used herein refers to a physicallydiscrete unit of agent appropriate for the patient to be treated. Itwill be understood, however, that the total daily usage of the compoundsand compositions of the present invention will be decided by theattending physician within the scope of sound medical judgment. Thespecific effective dose level for any particular patient or organismwill depend upon a variety of factors including the disorder beingtreated and the severity of the disorder; the activity of the specificcompound employed; the specific composition employed; the age, bodyweight, general health, sex and diet of the patient; the time ofadministration, route of administration, and rate of excretion of thespecific compound employed; the duration of the treatment; drugs used incombination or coincidental with the specific compound employed, andlike factors well known in the medical arts. The term “patient”, as usedherein, means an animal, preferably a mammal, and most preferably ahuman.

The pharmaceutically acceptable compositions of this invention can beadministered to humans and other animals orally, rectally, parenterally,intracisternally, intravaginally, intraperitoneally, topically (as bypowders, ointments, or drops), bucally, as an oral or nasal spray, orthe like, depending on the severity of the infection being treated. Incertain embodiments, the compounds of the invention may be administeredorally or parenterally at dosage levels of about 0.01 mg/kg to about 50mg/kg and preferably from about 1 mg/kg to about 25 mg/kg, of subjectbody weight per day, one or more times a day, to obtain the desiredtherapeutic effect.

Liquid dosage forms for oral administration include, but are not limitedto, pharmaceutically acceptable emulsions, microemulsions, solutions,suspensions, syrups and elixirs. In addition to the active compounds,the liquid dosage forms may contain inert diluents commonly used in theart such as, for example, water or other solvents, solubilizing agentsand emulsifiers such as ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butylene glycol, dimethylformamide, oils (in particular,cottonseed, groundnut, corn, germ, olive, castor, and sesame oils),glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fattyacid esters of sorbitan, and mixtures thereof. Besides inert diluents,the oral compositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, and perfumingagents.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium prior to use.

In order to prolong the effect of a compound of the present invention,it is often desirable to slow the absorption of the compound fromsubcutaneous or intramuscular injection. This may be accomplished by theuse of a liquid suspension of crystalline or amorphous material withpoor water solubility. The rate of absorption of the compound thendepends upon its rate of dissolution that, in turn, may depend uponcrystal size and crystalline form. Alternatively, delayed absorption ofa parenterally administered compound form is accomplished by dissolvingor suspending the compound in an oil vehicle. Injectable depot forms aremade by forming microencapsule matrices of the compound in biodegradablepolymers such as polylactide-polyglycolide. Depending upon the ratio ofcompound to polymer and the nature of the particular polymer employed,the rate of compound release can be controlled. Examples of otherbiodegradable polymers include poly(orthoesters) and poly(anhydrides).Depot injectable formulations are also prepared by entrapping thecompound in liposomes or microemulsions that are compatible with bodytissues.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat ambient temperature but liquid at body temperature and therefore meltin the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like. The solid dosage forms of tablets, dragees, capsules, pills,and granules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions that can be usedinclude polymeric substances and waxes. Solid compositions of a similartype may also be employed as fillers in soft and hard-filled gelatincapsules using such excipients as lactose or milk sugar as well as highmolecular weight polethylene glycols and the like.

The active compounds can also be in micro-encapsulated form with one ormore excipients as noted above. The solid dosage forms of tablets,dragees, capsules, pills, and granules can be prepared with coatings andshells such as enteric coatings, release controlling coatings and othercoatings well known in the pharmaceutical formulating art. In such soliddosage forms the active compound may be admixed with at least one inertdiluent such as sucrose, lactose or starch. Such dosage forms may alsocomprise, as is normal practice, additional substances other than inertdiluents, e.g., tableting lubricants and other tableting aids such amagnesium stearate and microcrystalline cellulose. In the case ofcapsules, tablets and pills, the dosage forms may also comprisebuffering agents. They may optionally contain opacifying agents and canalso be of a composition that they release the active ingredient(s)only, or preferentially, in a certain part of the intestinal tract,optionally, in a delayed manner. Examples of embedding compositions thatcan be used include polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound ofthis invention include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as may be required.Ophthalmic formulation, ear drops, and eye drops are also contemplatedas being within the scope of this invention. Additionally, the presentinvention contemplates the use of transdermal patches, which have theadded advantage of providing controlled delivery of a compound to thebody. Such dosage forms can be made by dissolving or dispensing thecompound in the proper medium. Absorption enhancers can also be used toincrease the flux of the compound across the skin. The rate can becontrolled by either providing a rate controlling membrane or bydispersing the compound in a polymer matrix or gel.

According to one embodiment, the invention relates to a method ofinhibiting ACC in a biological sample comprising the step of contactingsaid biological sample with a compound of this invention, or acomposition comprising said compound.

In certain embodiments, the invention relates to a method of modulatingfatty acid levels in a biological sample comprising the step ofcontacting said biological sample with a compound of this invention, ora composition comprising said compound.

The term “biological sample”, as used herein, includes, withoutlimitation, cell cultures or extracts thereof; biopsied materialobtained from a mammal or extracts thereof and blood, saliva, urine,feces, semen, tears, or other body fluids or extracts thereof.

Inhibition of enzymes in a biological sample is useful for a variety ofpurposes that are known to one of skill in the art. Examples of suchpurposes include, but are not limited to biological assays, geneexpression studies, and biological target identification.

Another embodiment of the present invention relates to a method ofinhibiting ACC in a patient comprising the step of administering to saidpatient a compound of the present invention, or a composition comprisingsaid compound.

According to another embodiment, the invention relates to a method ofinhibiting fatty acid production, stimulating fatty acid oxidation, orboth, in a patient comprising the step of administering to said patienta compound of the present invention, or a composition comprising saidcompound. According to certain embodiments, the invention relates to amethod of inhibiting fatty acid production, stimulating fatty acidoxidation, or both in a patient, leading to decreasing obesity oralleviating symptoms of metabolic syndrome, comprising the step ofadministering to said patient a compound of the present invention, or acomposition comprising said compound. In other embodiments, the presentinvention provides a method for treating a disorder mediated by ACC, ina patient in need thereof, comprising the step of administering to saidpatient a compound according to the present invention orpharmaceutically acceptable composition thereof. Such disorders aredescribed in detail herein.

In some embodiments the compounds and compositions of the presentinvention may be used in a method of treating obesity or anothermetabolic disorder. In certain embodiments the compounds andcompositions of the present invention may be used to treat obesity orother metabolic disorder in a mammal. In certain embodiments the mammalis a human patient. In certain embodiments the compounds andcompositions of the present invention may be used to treat obesity orother metabolic disorder in a human patient.

In some embodiments the present invention provides a method of treatingobesity or another metabolic disorder, comprising administering acompound or composition of the present invention to a patient withobesity or another metabolic disorder. In certain embodiments the methodof treating obesity or another metabolic disorder comprisesadministering compounds and compositions of the present invention to amammal. In certain embodiments the mammal is a human. In someembodiments the metabolic disorder is dyslipidemia, type IIIdyslipidemia, or hyperlipidemia. In some embodiments the hyperlipidemiais hypertriglyceridemia. In some embodiments, the obesity is a symptomof Prader-Willi syndrome, Bardet-Biedl syndrome, Cohen syndrome or MOMOsyndrome. In some embodiments, the obesity is a side effect of theadministration of another medication, including but not limited toinsulin, sulfunylureas, thiazolidinediones, antipsychotics,antidepressants, steroids, anticonvulsants (including phenytoin andvalproate), pizotifen, or hormonal contraceptives.

In certain embodiments, the present invention provides a method oftreating cancer or another proliferative disorder, comprisingadministering a compound or composition of the present invention to apatient with cancer or another proliferative disorder. In certainembodiments, the method of treating cancer or another proliferativedisorder comprises administering compounds and compositions of thepresent invention to a mammal. In certain embodiments, the mammal is ahuman.

As used herein, the terms “inhibition of cancer” and “inhibition ofcancer cell proliferation” refer to the inhibition of the growth,division, maturation or viability of cancer cells, and/or causing thedeath of cancer cells, individually or in aggregate with other cancercells, by cytotoxicity, nutrient depletion, or the induction ofapoptosis.

Examples of tissues containing cancerous cells whose proliferation isinhibited by the compounds and compositions described herein and againstwhich the methods described herein are useful include but are notlimited to breast, prostate, brain, blood, bone marrow, liver, pancreas,skin, kidney, colon, ovary, lung, testicle, penis, thyroid, parathyroid,pituitary, thymus, retina, uvea, conjunctiva, spleen, head, neck,trachea, gall bladder, rectum, salivary gland, adrenal gland, throat,esophagus, lymph nodes, sweat glands, sebaceous glands, muscle, heart,and stomach.

In some embodiments, the cancer treated by compounds or compositions ofthe invention is a melanoma, liposarcoma, lung cancer, breast cancer,prostate cancer, leukemia, kidney cancer, esophageal cancer, braincancer, lymphoma or colon cancer. In certain embodiments, the cancer isa primary effusion lymphoma (PEL). In certain preferred embodiments thecancer to be treated by compounds or compositions of the invention isone bearing an activated MAPK pathway. In some embodiments the cancerbearing an activated MAPK pathway is a melanoma. In certain preferredembodiments the cancer treated by compounds or compositions of theinvention is one associated with BRCA1 mutation. In an especiallypreferred embodiment, the cancer treated by compounds or compositions ofthe invention is a triple negative breast cancer. In some embodiments,the lung cancer is non-small cell lung cancer (NSCLC).

In certain embodiments, the disease which can be treated by compounds ofthe invention are neurological disorders. In some embodiments, theneurological disorder is Alzheimer's Disease, Parkinson's Disease,epilepsy, ischemia, Age Associated Memory Impairment, Mild CognitiveImpairment, Friedreich's Ataxia, GLUT1-deficient epilepsy,Leprechaunism, Rabson-Mendenhall Syndrome, Coronary Arterial BypassGraft dementia, anaesthesia-induced memory loss, amyotrophic lateralsclerosis, gliomaor Huntington's Disease.

In certain embodiments, the disease which can be treated by compounds ofthe invention is an infectious disease. In some embodiments, theinfectious disease is a viral infection. In some embodiments the viralinfection is cytomegalovirus infection or influenza infection. In someembodiments, the infectious disease is a fungal infection. In someembodiments, the infectious disease is a bacterial infection.

Depending upon the particular condition, or disease, to be treated,additional therapeutic agents, which are normally administered to treatthat condition, may be administered in combination with compounds andcompositions of this invention. As used herein, additional therapeuticagents that are normally administered to treat a particular disease, orcondition, are known as “appropriate for the disease, or condition,being treated”.

In certain embodiments, a provided compound, or composition thereof, isadministered in combination with another inhibitor of ACC or antiobesityagent. In some embodiments, a provided compound, or composition thereof,is administered in combination with one or more other therapeuticagents. Such therapeutic agents agents include, but are not limited toagents such as orlistat (Xenical), CNS stimulants, Qsymia, or Belviq.

In certain embodiments, a provided compound, or a composition thereof,is administered in combination with another anti-cancer, cytotoxin, orchemotherapeutic agent, to a patient in need thereof.

In certain embodiments, the anti-cancer or chemotherapeutic agents usedin combination with compounds or compositions of the invention include,but are not limited to metformin, phenformin, buformin, imatinib,nilotinib, gefitinib, sunitinib, carfilzomib, salinosporamide A,retinoic acid, cisplatin, carboplatin, oxaliplatin, mechlorethamine,cyclophosphamide, chlorambucil, ifosfamide, azathioprine,mercaptopurine, doxifluridine, fluorouracil, gemcitabine, methotrexate,tioguanine, vincristine, vinblastine, vinorelbine, vindesine,podophyllotoxin, etoposide, teniposide, tafluposide, paclitaxel,docetaxel, irinotecan, topotecan, amsacrine, actinomycin, doxorubicin,daunorubicin, valrubicin, idarubicin, epirubicin, plicamycin, mitomycin,mitoxantrone, melphalan, busulfan, capecitabine, pemetrexed,epothilones, 13-cis-Retinoic Acid, 2-CdA, 2-Chlorodeoxyadenosine,5-Azacitidine, 5-Fluorouracil, 5-FU, 6-Mercaptopurine, 6-MP, 6-TG,6-Thioguanine, Abraxane, Accutane®, Actinomycin-D, Adriamycin®,Adrucil®, Afinitor®, Agrylin®, Ala-Cort®, Aldesleukin, Alemtuzumab,ALIMTA, Alitretinoin, Alkaban-AQ®, Alkeran®, All-transretinoic Acid,Alpha Interferon, Altretamine, Amethopterin, Amifostine,Aminoglutethimide, Anagrelide, Anandron®, Anastrozole,Arabinosylcytosine, Ara-C, Aranesp®, Aredia®, Arimidex®, Aromasin®,Arranon®, Arsenic Trioxide, Arzerra™, Asparaginase, ATRA, Avastin®,Azacitidine, BCG, BCNU, Bendamustine, Bevacizumab, Bexarotene, BEXXAR®,Bicalutamide, BiCNU, Blenoxane®, Bleomycin, Bortezomib, Busulfan,Busulfex®, C225, Calcium Leucovorin, Campath®, Camptosar®,Camptothecin-11, Capecitabine, Carac™, Carboplatin, Carmustine,Carmustine Wafer, Casodex®, CC-5013, CCI-779, CCNU, CDDP, CeeNU,Cerubidine®, Cetuximab, Chlorambucil, Citrovorum Factor, Cladribine,Cortisone, Cosmegen®, CPT-11, Cytadren®, Cytosar-U®, Cytoxan®,Dacarbazine, Dacogen, Dactinomycin, Darbepoetin Alfa, Dasatinib,Daunomycin, Daunorubicin Hydrochloride, Daunorubicin Liposomal,DaunoXome®, Decadron, Decitabine, Delta-Cortef®, Deltasone®, Denileukin,Diftitox, DepoCyt™, Dexamethasone, Dexamethasone Acetate, DexamethasoneSodium Phosphate, Dexasone, Dexrazoxane, DHAD, DIC, Diodex, Docetaxel,Doxil®, Doxorubicin, Doxorubicin Liposomal, Droxia™, DTIC, DTIC-Dome®,Duralone®, Efudex®, Eligard™, Ellence™, Eloxatin™, Elspar®, Emcyt®,Epirubicin, Epoetin Alfa, Erbitux, Erlotinib, Erwinia L-asparaginase,Estramustine, Ethyol, Etopophos®, Etoposide, Etoposide Phosphate,Eulexin®, Everolimus, Evista®, Exemestane, Fareston®, Faslodex®,Femara®, Filgrastim, Floxuridine, Fludara®, Fludarabine, Fluoroplex®,Fluorouracil, Fluorouracil (cream), Fluoxymesterone, Flutamide, FolinicAcid, FUDR®, Fulvestrant, G-CSF, Gefitinib, Gemcitabine, Gemtuzumab,ozogamicin, Gemzar Gleevec™, Gliadel® Wafer, GM-CSF, Goserelin,Granulocyte—Colony Stimulating Factor, Granulocyte Macrophage ColonyStimulating Factor, Halotestin®, Herceptin®, Hexadrol, Hexalen®,Hexamethylmelamine, HMM, Hycamtin®, Hydrea®, Hydrocort Acetate®,Hydrocortisone, Hydrocortisone Sodium Phosphate, Hydrocortisone SodiumSuccinate, Hydrocortone Phosphate, Hydroxyurea, Ibritumomab,Ibritumomab, Tiuxetan, Idamycin®, Idarubicin Ifex®, IFN-alpha,Ifosfamide, IL-11, IL-2, Imatinib mesylate, Imidazole Carboxamide,Interferon alfa, Interferon Alfa-2b (PEG Conjugate), Interleukin-2,Interleukin-11, Intron A® (interferon alfa-2b), Iressa®, Irinotecan,Isotretinoin, Ixabepilone, Ixempra™, Kidrolase®, Lanacort®, Lapatinib,L-asparaginase, LCR, Lenalidomide, Letrozole, Leucovorin, Leukeran,Leukine™, Leuprolide, Leurocristine, Leustatin™, Liposomal Ara-C, LiquidPred®, Lomustine, L-PAM, L-Sarcolysin, Lupron®, Lupron Depot®,Matulane®, Maxidex, Mechlorethamine, Mechlorethamine Hydrochloride,Medralone®, Medrol®, Megace®, Megestrol, Megestrol Acetate, Melphalan,Mercaptopurine, Mesna, Mesnex™, Methotrexate, Methotrexate Sodium,Methylprednisolone, Meticorten®, Mitomycin, Mitomycin-C, Mitoxantrone,M-Prednisol®, MTC, MTX, Mustargen®, Mustine, Mutamycin®, Myleran®,Mylocel™, Mylotarg®, Navelbine®, Nelarabine, Neosar®, Neulasta™,Neumega®, Neupogen®, Nexavar®, Nilandron®, Nilotinib, Nilutamide,Nipent®, Nitrogen Mustard, Novaldex®, Novantrone®, Nplate, Octreotide,Octreotide acetate, Ofatumumab, Oncospar®, Oncovin®, Ontak®, Onxal™,Oprelvekin, Orapred®, Orasone®, Oxaliplatin, Paclitaxel, PaclitaxelProtein-bound, Pamidronate, Panitumumab, Panretin®, Paraplatin®,Pazopanib, Pediapred®, PEG Interferon, Pegaspargase, Pegfilgrastim,PEG-INTRON™, PEG-L-asparaginase, PEMETREXED, Pentostatin, PhenylalanineMustard, Platinol®, Platinol-AQ®, Prednisolone, Prednisone, Prelone®,Procarbazine, PROCRIT®, Proleukin®, Prolifeprospan 20 with CarmustineImplant, Purinethol®, Raloxifene, Revlimid®, Rheumatrex®, Rituxan®,Rituximab, Roferon-A® (Interferon Alfa-2a), Romiplostim, Rubex®,Rubidomycin hydrochloride, Sandostatin®, Sandostatin LAR®, Sargramostim,Solu-Cortef®, Solu-Medrol®, Sorafenib, SPRYCEL™, STI-571, Streptozocin,SU11248, Sunitinib, Sutent®, Tamoxifen, Tarceva®, Targretin®, Tasigna®,Taxol®, Taxotere®, Temodar®, Temozolomide, Temsirolimus, Teniposide,TESPA, Thalidomide, Thalomid®, TheraCys®, Thioguanine, ThioguanineTabloid®, Thiophosphoamide, Thioplex®, Thiotepa, TICE®, Toposar®,Topotecan, Toremifene, Torisel®, Tositumomab, Trastuzumab, Treanda®,Tretinoin, Trexall™, Trisenox®, TSPA, TYKERB®, VCR, Vectibix™, Velban®,Velcade®, VePesid®, Vesanoid®, Viadur™, Vidaza®, Vinblastine,Vinblastine Sulfate, Vincasar Pfs®, Vincristine, Vinorelbine,Vinorelbine tartrate, VLB, VM-26, Vorinostat, Votrient, VP-16, Vumon®,Xeloda®, Zanosar®, Zevalin™, Zinecard®, Zoladex®, Zoledronic acid,Zolinza, Zometa®, or combinations of any of the above.

In certain embodiments, compounds of the present invention may beadministered together with a biguanide selected from metformin,phenformin, or buformin, to a patient in need thereof. In certainembodiments, the patient administered a combination of a compound of theinvention and a biguanide is suffering from a cancer, obesity, a liverdisease, diabetes or two or more of the above.

In certain embodiments, a combination of 2 or more therapeutic agentsmay be administered together with compounds of the invention. In certainembodiments, a combination of 3 or more therapeutic agents may beadministered with compounds of the invention.

Other examples of agents the inhibitors of this invention may also becombined with include, without limitation: vitamins and nutritionalsupplements, cancer vaccines, treatments for neutropenia (e.g. G-CSF,filgrastim, lenograstim), treatments for thrombocytopenia (e.g. bloodtransfusion, erythropoietin), PI3 kinase (PI3K) inhibitors, MEKinhibitors, mTOR inhibitors, CPT1 inhibitors, AMPK activators, PCSK9inhibitors, SREBP site 1 protease inhibitors, HMG CoA-reductaseinhibitors, antiemetics (e.g. 5-HT₃ receptor antagonists, dopamineantagonists, NK1 receptor antagonists, histamine receptor antagonists,cannabinoids, benzodiazepines, or anticholinergics), treatments forAlzheimer's Disease such as Aricept® and Excelon®; treatments forParkinson's Disease such as L-DOPA/carbidopa, entacapone, ropinrole,pramipexole, bromocriptine, pergolide, trihexephendyl, and amantadine;agents for treating Multiple Sclerosis (MS) such as beta interferon(e.g., Avonex® and Rebif), Copaxone®, and mitoxantrone; treatments forasthma such as albuterol and Singulair®; agents for treatingschizophrenia such as zyprexa, risperdal, seroquel, and haloperidol;anti-inflammatory agents such as corticosteroids, TNF blockers, IL-1 RA,azathioprine, cyclophosphamide, and sulfasalazine; immunomodulatory andimmunosuppressive agents such as cyclosporin, tacrolimus, rapamycin,mycophenolate mofetil, interferons, corticosteroids, cyclophophamide,azathioprine, and sulfasalazine; neurotrophic factors such asacetylcholinesterase inhibitors, MAO inhibitors, interferons,anticonvulsants, ion channel blockers, riluzole, and anti-Parkinsonianagents; agents for treating cardiovascular disease such asbeta-blockers, ACE inhibitors, diuretics, nitrates, calcium channelblockers, and statins, fibrates, cholesterol absorption inhibitors, bileacid sequestrants, and niacin; agents for treating liver disease such ascorticosteroids, cholestyramine, interferons, and anti-viral agents;agents for treating blood disorders such as corticosteroids,anti-leukemic agents, and growth factors; agents for treatingimmunodeficiency disorders such as gamma globulin; and anti-diabeticagents such as biguanides (metformin, phenformin, buformin),thiazolidinediones (rosiglitazone, pioglitazone, troglitazone),sulfonylureas (tolbutamide, acetohexamide, tolazamide, chlorpropamide,glipizide, glyburide, glimepiride, gliclazide), meglitinides(repaglinide, nateglinide), alpha-glucosidase inhibitors (miglitol,acarbose), incretin mimetics (exenatide, liraglutide, taspoglutide),gastric inhibitory peptide analogs, DPP-4 inhibitors (vildagliptin,sitagliptin, saxagliptin, linagliptin, alogliptin), amylin analogs(pramlintide), and insulin and insulin analogs.

In certain embodiments, compounds of the present invention, or apharmaceutically acceptable composition thereof, are administered incombination with antisense agents, a monoclonal or polyclonal antibodyor an siRNA therapeutic.

Those additional agents may be administered separately from an inventivecompound-containing composition, as part of a multiple dosage regimen.Alternatively, those agents may be part of a single dosage form, mixedtogether with a compound of this invention in a single composition. Ifadministered as part of a multiple dosage regime, the two active agentsmay be submitted simultaneously, sequentially or within a period of timefrom one another, normally within five hours from one another.

As used herein, the term “combination,” “combined,” and related termsrefers to the simultaneous or sequential administration of therapeuticagents in accordance with this invention. For example, a compound of thepresent invention may be administered with another therapeutic agentsimultaneously or sequentially in separate unit dosage forms or togetherin a single unit dosage form. Accordingly, the present inventionprovides a single unit dosage form comprising a compound of formula I,an additional therapeutic agent, and a pharmaceutically acceptablecarrier, adjuvant, or vehicle.

The amount of both, an inventive compound and additional therapeuticagent (in those compositions which comprise an additional therapeuticagent as described above) that may be combined with the carriermaterials to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration. Preferably,compositions of this invention should be formulated so that a dosage ofbetween 0.01-100 mg/kg body weight/day of an inventive can beadministered.

In those compositions which comprise an additional therapeutic agent,that additional therapeutic agent and the compound of this invention mayact synergistically. Therefore, the amount of additional therapeuticagent in such compositions will be less than that required in amonotherapy utilizing only that therapeutic agent. In such compositionsa dosage of between 0.01-100 μg/kg body weight/day of the additionaltherapeutic agent can be administered.

The amount of additional therapeutic agent present in the compositionsof this invention will be no more than the amount that would normally beadministered in a composition comprising that therapeutic agent as theonly active agent. Preferably the amount of additional therapeutic agentin the presently disclosed compositions will range from about 50% to100% of the amount normally present in a composition comprising thatagent as the only therapeutically active agent.

The invention further refers to an agricultural composition comprisingat least one compound of formula I as defined above or an agriculturallyacceptable salt thereof and a liquid or solid carrier. Suitablecarriers, as well as auxiliaries and further active compounds which mayalso be contained in the composition of the invention are defined below.

Suitable “agriculturally acceptable salts” include but are not limitedto the salts of those cations or the acid addition salts of those acidswhose cations and anions, respectively, have no adverse effect on thefungicidal action of the compounds of formula I. Thus, suitable cationsare in particular the ions of the alkali metals, preferably sodium andpotassium, of the alkaline earth metals, preferably calcium, magnesiumand barium, and of the transition metals, preferably manganese, copper,zinc and iron, and also the ammonium ion which, if desired, may carryone to four C₁-C₄-alkyl substituents and/or one phenyl or benzylsubstituent, preferably diisopropylammonium, tetramethylammonium,tetrabutylammonium, trimethylbenzylammonium. Additional agriculturallyacceptable salts include phosphonium ions, sulfonium ions, preferablytri(C₁-C₄-alkyl)sulfonium and sulfoxonium ions, preferablytri(C₁-C₄-alkyl)sulfoxonium. Anions of useful acid addition salts areprimarily chloride, bromide, fluoride, hydrogen-sulfate, sulfate,dihydrogenphosphate, hydrogenphosphate, phosphate, nitrate, bicarbonate,carbonate, hexafluorosilicate, hexafluorophosphate, benzoate, and alsothe anions of C₁-C₄-alkanoic acids, preferably formate, acetate,propionate and butyrate. Such agriculturally acceptable acid additionsalts can be formed by reacting compounds of formula I bearing a basicionizable group with an acid of the corresponding anion, preferablyhydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid ornitric acid.

The compounds of formula I and the compositions according to theinvention, respectively, are suitable as fungicides. They aredistinguished by an outstanding effectiveness against a broad spectrumof phytopathogenic fungi, including soil-borne fungi, which deriveespecially from the classes of the Plasmodiophoromycetes,Peronosporomycetes (syn. Oomycetes), Chytridiomycetes, Zygomycetes,Ascomycetes, Basidiomycetes and Deuteromycetes (syn. Fungi imperfecti).Some are systemically effective and they can be used in crop protectionas foliar fungicides, fungicides for seed dressing and soil fungicides.Moreover, they are suitable for controlling harmful fungi, which interalia occur in wood or roots of plants.

In some embodiments, the compounds of formula I and the compositionsaccording to the invention are particularly important in the control ofphytopathogenic fungi on various cultivated plants, such as cereals,e.g. wheat, rye, barley, triticale, oats or rice; beet, e.g. sugar beetor fodder beet; fruits, such as pomes, stone fruits or soft fruits, e.g.apples, pears, plums, peaches, almonds, cherries, strawberries,raspberries, blackberries or gooseberries; leguminous plants, such aslentils, peas, alfalfa or soybeans; oil plants, such as rape, mustard,olives, sunflowers, coconut, cocoa beans, castor oil plants, oil palms,ground nuts or soybeans; cucurbits, such as squashes, cucumber ormelons; fiber plants, such as cotton, flax, hemp or jute; citrus fruit,such as oranges, lemons, grapefruits or mandarins; vegetables, such asspinach, lettuce, asparagus, cabbages, carrots, onions, tomatoes,potatoes, cucurbits or paprika; lauraceous plants, such as avocados,cinnamon or camphor; energy and raw material plants, such as corn,soybean, rape, sugar cane or oil palm; corn; tobacco; nuts; coffee; tea;bananas; vines (table grapes and grape juice grape vines); hop; turf;natural rubber plants or ornamental and forestry plants, such asflowers, shrubs, broad-leaved trees or evergreens, e.g. conifers; and onthe plant propagation material, such as seeds, and the crop material ofthese plants.

In some embodiments, compounds of formula I and compositions thereof,respectively are used for controlling a multitude of fungi on fieldcrops, such as potatoes sugar beets, tobacco, wheat, rye, barley, oats,rice, corn, cotton, soybeans, rape, legumes, sunflowers, coffee or sugarcane; fruits; vines; ornamentals; or vegetables, such as cucumbers,tomatoes, beans or squashes.

The term “plant propagation material” is to be understood to denote allthe generative parts of the plant such as seeds and vegetative plantmaterial such as cuttings and tubers (e.g. potatoes), which can be usedfor the multiplication of the plant. This includes seeds, roots, fruits,tubers, bulbs, rhizomes, shoots, sprouts and other parts of plants,including seedlings and young plants, which are to be transplanted aftergermination or after emergence from soil. These young plants may also beprotected before transplantation by a total or partial treatment byimmersion or pouring.

In some embodiments, treatment of plant propagation materials withcompounds of formula I and compositions thereof, respectively, is usedfor controlling a multitude of fungi on cereals, such as wheat, rye,barley and oats; rice, corn, cotton and soybeans.

The term “cultivated plants” is to be understood as including plantswhich have been modified by breeding, mutagenesis or genetic engineeringincluding but not limiting to agricultural biotech products on themarket or in development. Genetically modified plants are plants, whichgenetic material has been so modified by the use of recombinant DNAtechniques that under natural circumstances cannot readily be obtainedby cross breeding, mutations or natural recombination. Typically, one ormore genes have been integrated into the genetic material of agenetically modified plant in order to improve certain properties of theplant. Such genetic modifications also include but are not limited totargeted post-translational modification of protein(s), oligo- orpolypeptides e.g. by glycosylation or polymer additions such asprenylated, acetylated or farnesylated moieties or PEG moieties.

Plants that have been modified by breeding, mutagenesis or geneticengineering, e.g. have been rendered tolerant to applications ofspecific classes of herbicides, such as hydroxyphenylpyruvatedioxygenase (HPPD) inhibitors; acetolactate synthase (ALS) inhibitors,such as sulfonyl ureas (see e.g. U.S. Pat. No. 6,222,100, WO 01/82685,WO 00/26390, WO 97/41218, WO 98/02526, WO 98/02527, WO 04/106529, WO05/20673, WO 03/14357, WO 03/13225, WO 03/14356, WO 04/16073) orimida-zolinones (see e.g. U.S. Pat. No. 6,222,100, WO 01/82685, WO00/026390, WO 97/41218, WO 98/002526, WO 98/02527, WO 04/106529, WO05/20673, WO 03/014357, WO 03/13225, WO 03/14356, WO 04/16073);enolpyruvylshikimate-3-phosphate synthase (EPSPS) inhibitors, such asglyphosate (see e.g. WO 92/00377); glutamine synthetase (GS) inhibitors,such as glufosinate (see e.g. EP-A 242 236, EP-A 242 246) or oxynilherbicides (see e.g. U.S. Pat. No. 5,559,024) as a result ofconventional methods of breeding or genetic engineering. Severalcultivated plants have been rendered tolerant to herbicides byconventional methods of breeding (mutagenesis), e.g. Clearfield® summerrape (Canola, BASF SE, Germany) being tolerant to imidazolinones, e.g.imazamox. Genetic engineering methods have been used to rendercultivated plants, such as soybean, cotton, corn, beets and rape,tolerant to herbicides such as glyphosate and glufosinate, some of whichare commercially available under the trade names RoundupReady®(glyphosate-tolerant, Monsanto, U.S.A.) and LibertyLink®(glufosinate-tolerant, Bayer CropScience, Germany).

Furthermore, plants are also covered that, by the use of recombinant DNAtechniques, are capable to synthesize one or more insecticidal proteins,especially those known from the bacterial genus Bacillus, particularlyfrom Bacillus thuringiensis, such as δ-endotoxins, e.g. CrylA(b),CrylA(c), CrylF, CrylF(a2), CryllA(b), CrylllA, CrylllB(bi) or Cryθc;vegetative insecticidal proteins (VIP), e.g. VIP1, VIP2, VIP3 or VIP3A;insecticidal proteins of bacteria colonizing nematodes, e.g.Photorhabdus spp. or Xenor-habdus spp.; toxins produced by animals, suchas scorpion toxins, arachnid toxins, wasp toxins, or otherinsect-specific neurotoxins; toxins produced by fungi, suchStreptomycetes toxins, plant lectins, such as pea or barley lectins;agglutinins; proteinase inhibitors, such as trypsin inhibitors, serineprotease inhibitors, patatin, cystatin or pa-pain inhibitors;ribosome-inactivating proteins (RIP), such as ricin, maize-RIP, abrin,luffin, saporin or bryodin; steroid metabolism enzymes, such as3-hydroxysteroid oxidase, ecdysteroid-IDP-glycosyl-transferase,cholesterol oxidases, ecdysone inhibitors or HMG-CoA-reductase; ionchannel blockers, such as blockers of sodium or calcium channels;juvenile hormone esterase; diuretic hormone receptors (helicokininreceptors); stilben synthase, bibenzyl synthase, chitinases orglucanases. In the context of the present invention these insecticidalproteins or toxins are to be understood expressly also as pre-toxins,hybrid proteins, truncated or otherwise modified proteins. Hybridproteins are characterized by a new combination of protein domains,(see, e.g. WO 02/015701). Further examples of such toxins or geneticallymodified plants capable of synthesizing such toxins are disclosed, e.g.,in EP-A 374 753, WO 93/007278, WO 95/34656, EP-A 427 529, EP-A 451 878,WO 03/18810 und WO 03/52073. The methods for producing such geneticallymodified plants are generally known to the person skilled in the art andare described, e.g., in the publications mentioned above. Theseinsecticidal proteins contained in the genetically modified plantsimpart to the plants producing these proteins tolerance to harmful pestsfrom all taxonomic groups of arthropods, especially to beetles(Coleoptera), two-winged insects (Diptera), and moths (Lepidoptera) andto nematodes (Nematoda). Genetically modified plants capable tosynthesize one or more insecticidal proteins are, e.g., described in thepublications mentioned above, and some of them are commerciallyavailable such as YieldGard® (corn cultivars producing the CryiAbtoxin), YieldGard® Plus (corn cultivars producing Cry1 Ab and Cry3Bb1toxins), Starlink® (corn cultivars producing the Cry9c toxin),Her-Culex® RW (corn cultivars producing Cry34Ab1, Cry35Ab1 and theenzyme Phosphi-nothricin-N-Acetyltransferase [PAT]); NuCOTN® 33B (cottoncultivars producing the Cry1 Ac toxin), Bollgard® I (cotton cultivarsproducing the CryiAc toxin), Bollgard® Il (cotton cultivars producingCryiAc and Cry2Ab2 toxins); VIPCOT® (cotton cultivars producing aVIP-toxin); NewLeaf® (potato cultivars producing the Cry3A toxin);Bt-Xtra®, NatureGard®, KnockOut®, BiteGard®, Protecta®, Bt 1 1 (e.g.Agrisure® CB) and Bt176 from Syngenta Seeds SAS, France, (corn cultivarsproducing the CryiAb toxin and PAT enyzme), MIR604 from Syngenta SeedsSAS, France (corn cultivars producing a modified version of the Cry3Atoxin, c.f. WO 03/018810), MON 863 from Monsanto Europe S.A., Belgium(corn cultivars producing the Cry3Bbl toxin), IPC 531 from MonsantoEurope S.A., Belgium (cotton cultivars producing a modified version ofthe CryiAc toxin) and 1507 from Pioneer Overseas Corporation, Belgium(corn cultivars producing the Cry1 F toxin and PAT enzyme).

Furthermore, plants are also covered that, by the use of recombinant DNAtechniques, are capable to synthesize one or more proteins to increasethe resistance or tolerance of those plants to bacterial, viral orfungal pathogens. Examples of such proteins are the so-called“pathogenesis-related proteins” (PR proteins, see, e.g. EP-A 392225),plant disease resistance genes (e.g. potato cultivars, which expressresistance genes acting against Phytophthora infestans derived from theMexican wild potato Solanum bulbocastanum) or T4-lysozym (e.g. potatocultivars capable of synthesizing these proteins with increasedresistance against bacteria such as Erwinia amylvora). The methods forproducing such genetically modified plants are generally known to theperson skilled in the art and are described, e.g., in the publicationsmentioned above.

Furthermore, plants are also covered that, by the use of recombinant DNAtechniques, are capable to synthesize one or more proteins to increasethe productivity (e.g. biomass production, grain yield, starch content,oil content or protein content), tolerance to drought, salinity or othergrowth-limiting environmental factors or tolerance to pests and fungal,bacterial or viral pathogens of those plants.

Furthermore, plants are also covered that, by the use of recombinant DNAtechniques, contain a modified amount of substances of content or newsubstances of content, specifically to improve human or animalnutrition, e.g. oil crops that produce health-promoting long-chainomega-3 fatty acids or unsaturated omega-9 fatty acids (e.g. Nexera®rape, DOW Agro Sciences, Canada).

Furthermore, plants are also covered that, by the use of recombinant DNAtechniques, contain a modified amount of substances of content or newsubstances of content, specifically to improve raw material production,e.g. potatoes that produce increased amounts of amylopectin (e.g.Amflora® potato, BASF SE, Germany).

The compounds of formula I and compositions thereof, respectively, areparticularly suitable for controlling the following plant diseases:

Albugo spp. (white rust) on ornamentals, vegetables (e.g. A. Candida)and sunflowers (e.g. A. tragopogonis); Altemaria spp. (Alternaria leafspot) on vegetables, rape {A. brassicola or brassicae), sugar beets (A.tenuis), fruits, rice, soybeans, potatoes (e.g. A. solani or A.alternata), tomatoes (e.g. A. solani or A. alternata) and wheat;Aphanomyces spp. on sugar beets and vegetables; Ascochyta spp. oncereals and vegetables, e.g. A. tritici (anthracnose) on wheat and A.hordei on barley; Bipolaris and Drechslera spp. (teleomorph:Cochliobolus spp.), e.g. Southern leaf blight (D. maydis) or Northernleaf blight (β. zeicola) on corn, e.g. spot blotch (β. sorokiniana) oncereals and e.g. B. oryzae on rice and turfs; Blumeria (formerlyErysiphe) graminis (powdery mildew) on cereals (e.g. on wheat orbarley); Botrytis cinerea (teleomorph: Botryotinia fuckeliana: greymold) on fruits and berries (e.g. strawberries), vegetables (e.g.lettuce, carrots, celery and cabbages), rape, flowers, vines, forestryplants and wheat; Bremia lactucae (downy mildew) on lettuce;Ceratocystis (syn. Ophiostoma) spp. (rot or wilt) on broad-leaved treesand evergreens, e.g. C. ulmi (Dutch elm disease) on elms; Cercosporaspp. (Cercospora leaf spots) on corn (e.g. Gray leaf spot: C.zeaemaydis), rice, sugar beets (e.g. C. beticola), sugar cane,vegetables, coffee, soybeans (e.g. C. sojina or C. kikuchii) and rice;Cladosporium spp. on tomatoes (e.g. C. fulvum: leaf mold) and cereals,e.g. C. herbarum (black ear) on wheat; Claviceps purpurea (ergot) oncereals; Cochliobolus (anamorph: Helminthosporium of Bipolaris) spp.(leaf spots) on corn (C. carbonum), cereals (e.g. C. sativus, anamorph:B. sorokiniana) and rice (e.g. C. miyabeanus, anamorph: H. oryzae);Colletotrichum (teleomorph: Glomerella) spp. (an-thracnose) on cotton(e.g. C. gossypii), corn (e.g. C. graminicola: Anthracnose stalk rot),soft fruits, potatoes (e.g. C. coccodes: black dot), beans (e.g. C.lindemuthianum) and soybeans (e.g. C. truncatum or C. gloeosporioides);Corticium spp., e.g. C. sasakii (sheath blight) on rice; Corynesporacassiicola (leaf spots) on soybeans and ornamentals; Cycloconium spp.,e.g. C. oleaginum on olive trees; Cylindrocarpon spp. (e.g. fruit treecanker or young vine decline, teleomorph: Nectria or Neonectria spp.) onfruit trees, vines (e.g. C. liriodendri, teleomorph: Neonectrialiriodendri. Black Foot Disease) and ornamentals; Dematophora(teleomorph: Rosellinia) necatrix (root and stem rot) on soybeans;Diaporthe spp., e.g. D. phaseolorum (damping off) on soybeans;Drechslera (syn. Helminthosporium, teleomorph: Pyrenophora) spp. oncorn, cereals, such as barley (e.g. D. teres, net blotch) and wheat(e.g. D. tritici-repentis: tan spot), rice and turf; Esca (dieback,apoplexy) on vines, caused by Formitiporia (syn. Phellinus) punctata, F.mediterranea, Phaeomoniella chlamydospora (earlier Phaeoacremoniumchlamydosporum), Phaeoacremonium aleophilum and/or Botryosphaeriaobtusa; Elsinoe spp. on pome fruits (E. gyri), soft fruits (E. veneta:anthracnose) and vines (E ampelina: anthracnose); Entyloma oryzae (leafsmut) on rice; Epicoccum spp. (black mold) on wheat; Erysiphe spp.(powdery mildew) on sugar beets (E. betae), vegetables (e.g. E. pisi),such as cucurbits (e.g. E. cichoracearum), cabbages, rape (e.g. E.cruciferarum); Eutypa lata (Eutypa canker or dieback, anamorph:Cytosporina lata, syn. Libertella blepharis) on fruit trees, vines andornamental woods; Exserohilum (syn. Helminthosporium) spp. on corn (e.g.E. turcicum); Fusarium (teleomorph: Gibberella) spp. (wilt, root or stemrot) on various plants, such as F. graminearum or F. culmorum (root rot,scab or head blight) on cereals (e.g. wheat or barley), F. oxysporum ontomatoes, F. solani on soybeans and F. verticillioides on corn;Gaeumannomyces graminis (take-all) on cereals (e.g. wheat or barley) andcorn; Gibberella spp. on cereals (e.g. G. zeae) and rice (e.g. G.fujikuroi: Bakanae disease); Glomerella cingulata on vines, pome fruitsand other plants and G. gossypii on cotton; Grain-staining complex onrice; Guignardia bidwellii (black rot) on vines; Gymnosporangium spp. onrosaceous plants and junipers, e.g. G. sabinae (rust) on pears;Helminthosporium spp. (syn. Drechslera, teleomorph: Cochliobolus) oncorn, cereals and rice; Hemileia spp., e.g. H. vastatrix (coffee leafrust) on coffee; lsariopsis clavispora (syn. Cladosporium vitis) onvines; Macrophomina phaseolina (syn. phaseoli) (root and stem rot) onsoybeans and cotton; Microdochium (syn. Fusarium) nivale (pink snowmold) on cereals (e.g. wheat or barley); Microsphaera diffusa (powderymildew) on soybeans; Monilinia spp., e.g. M. laxa, M. fructicola and M.fructigena (bloom and twig blight, brown rot) on stone fruits and otherrosaceous plants; Mycosphaerella spp. on cereals, bananas, soft fruitsand ground nuts, such as e.g. M. graminicola (anamorph: Septoriatritici, Septoria blotch) on wheat or M. fijiensis (black Sigatokadisease) on bananas; Peronospora spp. (downy mildew) on cabbage (e.g. P.brassicae), rape (e.g. P. parasitica), onions (e.g. P. destructor),tobacco (P. tabacina) and soybeans (e.g. P. manshurica); Phakopsorapachyrhizi and P. meibomiae (soybean rust) on soybeans; Phialophora spp.e.g. on vines (e.g. P. tracheiphila and P. tetraspora) and soybeans(e.g. P. gregata: stem rot); Phoma lingam (root and stem rot) on rapeand cabbage and P. betae (root rot, leaf spot and damping-off) on sugarbeets; Phomopsis spp. on sunflowers, vines (e.g. P. viticola: can andleaf spot) and soybeans (e.g. stem rot: P. phaseoli, teleomorph:Diaporthe phaseolorum); Physoderma maydis (brown spots) on corn;Phytophthora spp. (wilt, root, leaf, fruit and stem root) on variousplants, such as paprika and cucurbits (e.g. P. capsici), soybeans (e.g.P. megasperma, syn. P. sojae), potatoes and tomatoes (e.g. P. infestans:late blight) and broad-leaved trees (e.g. P. ramorum: sudden oak death);Plasmodiophora brassicae (club root) on cabbage, rape, radish and otherplants; Plasmopara spp., e.g. P. viticola (grapevine downy mildew) onvines and P. halstediiou sunflowers; Podosphaera spp. (powdery mildew)on rosaceous plants, hop, pome and soft fruits, e.g. P. leucotricha onapples; Polymyxa spp., e.g. on cereals, such as barley and wheat (P.graminis) and sugar beets (P. betae) and thereby transmitted viraldiseases; Pseudocercosporella herpotrichoides (eyespot, teleomorph:Tapesia yallundae) on cereals, e.g. wheat or barley; Pseudoperonospora(downy mildew) on various plants, e.g. P. cubensis on cucurbits or P.humili on hop; Pseudopezicula tracheiphila (red fire disease or,rotbrenner', anamorph: Phialo-phora) on vines; Puccinia spp. (rusts) onvarious plants, e.g. P. triticina (brown or leaf rust), P. striiformis(stripe or yellow rust), P. hordei (dwarf rust), P. graminis (stem orblack rust) or P. recondita (brown or leaf rust) on cereals, such ase.g. wheat, barley or rye, and asparagus (e.g. P. asparagi); Pyrenophora(anamorph: Drechslera) tritici-repentis (tan spot) on wheat or P. feres(net blotch) on barley; Pyricularia spp., e.g. P. oryzae (teleomorph:Magnaporthe grisea, rice blast) on rice and P. grisea on turf andcereals; Pythium spp. (damping-off) on turf, rice, corn, wheat, cotton,rape, sunflowers, soybeans, sugar beets, vegetables and various otherplants (e.g. P. ultimum or P. aphanidermatum); Ramularia spp., e.g. R.collo-cygni (Ramularia leaf spots, Physiological leaf spots) on barleyand R. beticola on sugar beets; Rhizoctonia spp. on cotton, rice,potatoes, turf, corn, rape, potatoes, sugar beets, vegetables andvarious other plants, e.g. R. solani (root and stem rot) on soybeans, R.solani (sheath blight) on rice or R. cerealis (Rhizoctonia springblight) on wheat or barley; Rhizopus stolonifer (black mold, soft rot)on strawberries, carrots, cabbage, vines and tomatoes; Rhynchosporiumsecalis (scald) on barley, rye and triticale; Sarocladium oryzae and S.attenuatum (sheath rot) on rice; Sclerotinia spp. (stem rot or whitemold) on vegetables and field crops, such as rape, sunflowers (e.g. S.sclerotiorum) and soybeans (e.g. S. rolfsii or S. sclerotiorum);Septoria spp. on various plants, e.g. S. glycines (brown spot) onsoybeans, S. tritici (Septoria blotch) on wheat and S. (syn.Stagonospora) nodorum (Stagonospora blotch) on cereals; Uncinula (syn.Erysiphe) necator (powdery mildew, anamorph: Oidium tuckeri) on vines;Setospaeria spp. (leaf blight) on corn (e.g. S. turcicum, syn.Helminthosporium turcicum) and turf; Sphacelotheca spp. (smut) on corn,(e.g. S. miliaria: head smut), sorghum and sugar cane; Sphaerothecafuliginea (powdery mildew) on cucurbits; Spongospora subterranea(powdery scab) on potatoes and thereby transmitted viral diseases;Stagonospora spp. on cereals, e.g. S. nodorum (Stagonospora blotch,teleomorph: Leptosphaeria [syn. Phaeosphaeria] nodorum) on wheat;Synchytrium endobioticum on potatoes (potato wart disease); Taphrinaspp., e.g. T. deformans (leaf curl disease) on peaches and T. pruni(plum pocket) on plums; Thielaviopsis spp. (black root rot) on tobacco,pome fruits, vegetables, soybeans and cotton, e.g. T. basicola (syn.Chalara elegans); Tilletia spp. (common bunt or stinking smut) oncereals, such as e.g. T. tritici (syn. T. caries, wheat bunt) and T.controversa (dwarf bunt) on wheat; Typhula incamata (grey snow mold) onbarley or wheat; Urocystis spp., e.g. U. occulta (stem smut) on rye;Uromyces spp. (rust) on vegetables, such as beans (e.g. U.appendiculatus, syn. U. phaseoli) and sugar beets (e.g. U. betae);Ustilago spp. (loose smut) on cereals (e.g. U. nuda and U. avaenae),corn (e.g. U. maydis: corn smut) and sugar cane; Venturia spp. (scab) onapples (e.g. V. inaequalis) and pears; and Verticillium spp. (wilt) onvarious plants, such as fruits and ornamentals, vines, soft fruits,vegetables and field crops, e.g. V. dahliae on strawberries, rape,potatoes and tomatoes.

The compounds of formula I and compositions thereof, respectively, arealso suitable for controlling harmful fungi in the protection of storedproducts or harvest and in the protection of materials. The term“protection of materials” is to be understood to denote the protectionof technical and non-living materials, such as adhesives, glues, wood,paper and paperboard, textiles, leather, paint dispersions, plastics,colling lubricants, fiber or fabrics, against the infestation anddestruction by harmful microorganisms, such as fungi and bacteria. As tothe protection of wood and other materials, the particular attention ispaid to the following harmful fungi: Ascomycetes such as Ophiostomaspp., Ceratocystis spp., Aureobasidium pullulans, Sclerophoma spp.,Chaetomium spp., Humicola spp., Petriella spp., Trichurus spp.;Basidiomycetes such as Coniophora spp., Coriolus spp., Gloeophyllumspp., Lentinus spp., Pleurotus spp., Poria spp., Serpula spp. andTyromyces spp., Deuteromycetes such as Aspergillus spp., Cladosporiumspp., Penicillium spp., Trichorma spp., Altemaria spp., Paecilomycesspp. and Zygomycetes such as Mucor spp., and in addition in theprotection of stored products and harvest the following yeast fungi areworthy of note: Candida spp. and Saccharomyces cerevisae.

The compounds of formula I and compositions thereof, respectively, maybe used for improving the health of a plant. The invention also relatesto a method for improving plant health by treating a plant, itspropagation material and/or the locus where the plant is growing or isto grow with an effective amount of compounds of formula I orcompositions thereof, respectively.

The term “plant health” is to be understood to denote a condition of theplant and/or its products which is determined by several indicatorsalone or in combination with each other such as yield (e.g. increasedbiomass and/or increased content of valuable ingredients), plant vigor(e.g. improved plant growth and/or greener leaves (“greening effect”)),quality (e.g. improved content or composition of certain ingredients)and tolerance to abiotic and/or biotic stress. The above identifiedindicators for the health condition of a plant may be interdependent ormay result from each other.

The compounds of formula I can be present in different crystalmodifications whose biological activity may differ. They are likewisesubject matter of the present invention.

The compounds of formula I are employed as such or in form ofcompositions by treating the fungi or the plants, plant propagationmaterials, such as seeds, soil, surfaces, materials or rooms to beprotected from fungal attack with a fungicidally effective amount of theactive substances. The application can be carried out both before andafter the infection of the plants, plant propagation materials, such asseeds, soil, surfaces, materials or rooms by the fungi.

Plant propagation materials may be treated with compounds of formula Ias such or a composition comprising at least one compound of formula Iprophylactically either at or before planting or transplanting.

The invention also relates to agrochemical compositions comprising asolvent or solid carrier and at least one compound of formula I and tothe use for controlling harmful fungi.

An agrochemical composition comprises a fungicidally effective amount ofa compound I and/or II. The term “effective amount” denotes an amount ofthe composition or of the compound of formula I, which is sufficient forcontrolling harmful fungi on cultivated plants or in the protection ofmaterials and which does not result in a substantial damage to thetreated plants. Such an amount can vary in a broad range and isdependent on various factors, such as the fungal species to becontrolled, the treated cultivated plant or material, the climaticconditions and the specific compound of formula I used.

The compounds of formula I and salts thereof can be converted intocustomary types of agrochemical compositions, e.g. solutions, emulsions,suspensions, dusts, powders, pastes and granules. The composition typedepends on the particular intended purpose; in each case, it shouldensure a fine and uniform distribution of the compound according to theinvention.

Examples for composition types are suspensions (SC, OD, FS),emulsifiable concentrates (EC), emulsions (EW, EO, ES), pastes,pastilles, wettable powders or dusts (WP, SP, SS, WS, DP, DS) orgranules (GR, FG, GG, MG), which can be water-soluble or wettable, aswell as gel formulations for the treatment of plant propagationmaterials such as seeds (GF).

Usually the composition types (e.g. SC, OD, FS, EC, WG, SG, WP, SP, SS,WS, GF) are employed diluted. Composition types such as DP, DS, GR, FG,GG and MG are usually used undiluted.

The compositions are prepared in a known manner (cf. U.S. Pat. No.3,060,084, EP-A 707 445 (for liquid concentrates), Browning:“Agglomeration”, Chemical Engineering, Dec. 4, 1967, 147-48, Perry'sChemical Engineer's Handbook, 4th Ed., McGraw-Hill, New York, 1963, pp.8-57 et seq., WO 91/13546, U.S. Pat. Nos. 4,172,714, 4,144,050,3,920,442, 5,180,587, 5,232,701, 5,208,030, GB 2,095,558, U.S. Pat. No.3,299,566, Klingman: Weed Control as a Science (J. Wiley & Sons, NewYork, 1961), Hance et al.: Weed Control Handbook (8th Ed., BlackwellScientific, Oxford, 1989) and Mollet, H. and Grubemann, A.: Formulationtechnology (Wiley VCH Verlag, Weinheim, 2001).

The agrochemical compositions may also comprise auxiliaries which arecustomary in agrochemical compositions. The auxiliaries used depend onthe particular application form and active substance, respectively.

Examples for suitable auxiliaries are solvents, solid carriers,dispersants or emulsifiers (such as further solubilizers, protectivecolloids, surfactants and adhesion agents), organic and inorganicthickeners, bactericides, anti-freezing agents, anti-foaming agents, ifappropriate colorants and tackifiers or binders (e.g. for seed treatmentformulations). Suitable solvents are water, organic solvents such asmineral oil fractions of medium to high boiling point, such as keroseneor diesel oil, furthermore coal tar oils and oils of vegetable or animalorigin, aliphatic, cyclic and aromatic hydrocarbons, e.g. toluene,xylene, paraffin, tetrahydronaphthalene, alkylated naphthalenes or theirderivatives, alcohols such as methanol, ethanol, propanol, butanol andcyclohexanol, glycols, ketones such as cyclohexanone andgamma-butyrolactone, fatty acid dimethylamides, fatty acids and fattyacid esters and strongly polar solvents, e.g. amines such asN-methylpyrrolidone.

Solid carriers are mineral earths such as silicates, silica gels, talc,kaolins, limestone, lime, chalk, bole, loess, clays, dolomite,diatomaceous earth, calcium sulfate, magnesium sulfate, magnesium oxide,ground synthetic materials, fertilizers, such as, e.g., ammoniumsulfate, ammonium phosphate, ammonium nitrate, ureas, and products ofvegetable origin, such as cereal meal, tree bark meal, wood meal andnutshell meal, cellulose powders and other solid carriers.

Suitable surfactants (adjuvants, wetters, tackifiers, dispersants oremulsifiers) are alkali metal, alkaline earth metal and ammonium saltsof aromatic sulfonic acids, such as ligninsoulfonic acid (Borresperse®types, Borregard, Norway) phenolsulfonic acid, naphthalenesulfonic acid(Morwet® types, Akzo Nobel, U.S.A.), dibutylnaphthalene-sulfonic acid(Nekal® types, BASF, Germany), and fatty acids, alkylsulfonates,alkyl-arylsulfonates, alkyl sulfates, laurylether sulfates, fattyalcohol sulfates, and sulfated hexa-, hepta- and octadecanolates,sulfated fatty alcohol glycol ethers, furthermore condensates ofnaphthalene or of naphthalenesulfonic acid with phenol and formaldehyde,polyoxy-ethylene octylphenyl ether, ethoxylated isooctylphenol,octylphenol, nonylphenol, alkylphenyl polyglycol ethers, tributylphenylpolyglycol ether, tristearyl-phenyl polyglycol ether, alkylarylpolyether alcohols, alcohol and fatty alcohol/ethylene oxidecondensates, ethoxylated castor oil, polyoxyethylene alkyl ethers,ethoxylated polyoxypropylene, lauryl alcohol polyglycol ether acetal,sorbitol esters, lignin-sulfite waste liquors and proteins, denaturedproteins, polysaccharides (e.g. methylcellulose), hydrophobicallymodified starches, polyvinyl alcohols (Mowiol® types, Clariant,Switzerland), polycarboxylates (Sokolan® types, BASF, Germany),polyalkoxylates, polyvinyl-amines (Lupasol® types, BASF, Germany),polyvinylpyrrolidone and the copolymers thereof.

Examples for thickeners (i.e. compounds that impart a modifiedflowability to compositions, i.e. high viscosity under static conditionsand low viscosity during agitation) are polysaccharides and organic andanorganic clays such as Xanthan gum (Kelzan®, CP Kelco, U.S.A.),Rhodopol® 23 (Rhodia, France), Veegum® (RT. Vanderbilt, U.S.A.) orAttaclay® (Engelhard Corp., NJ, USA).

Bactericides may be added for preservation and stabilization of thecomposition. Examples for suitable bactericides are those based ondichlorophene and benzylalcohol hemi formal (Proxel® from ICI orActicide® RS from Thor Chemie and Kathon® MK from Rohm & Haas) andisothiazolinone derivatives such as alkylisothiazolinones andbenzisothiazolinones (Acticide® MBS from Thor Chemie).

Examples for suitable anti-freezing agents are ethylene glycol,propylene glycol, urea and glycerin.

Examples for anti-foaming agents are silicone emulsions (such as e.g.Silikon® SRE, Wacker, Germany or Rhodorsil®, Rhodia, France), long chainalcohols, fatty acids, salts of fatty acids, fluoroorganic compounds andmixtures thereof

Suitable colorants are pigments of low water solubility andwater-soluble dyes. Examples to be mentioned and the designationsrhodamin B, C. I. pigment red 112, C. I. solvent red 1, pigment blue15:4, pigment blue 15:3, pigment blue 15:2, pigment blue 15:1, pigmentblue 80, pigment yellow 1, pigment yellow 13, pigment red 112, pigmentred 48:2, pigment red 48:1, pigment red 57:1, pigment red 53:1, pigmentorange 43, pigment orange 34, pigment orange 5, pigment green 36,pigment green 7, pigment white 6, pigment brown 25, basic violet 10,basic violet 49, acid red 51, acid red 52, acid red 14, acid blue 9,acid yellow 23, basic red 10, basic red 108.

Examples for tackifiers or binders are polyvinylpyrrolidons,polyvinylacetates, polyvinyl alcohols and cellulose ethers (Tylose®,Shin-Etsu, Japan).

Powders, materials for spreading and dusts can be prepared by mixing orconcomitantly grinding the compounds of formula I and, if appropriate,further active substances, with at least one solid carrier.

Granules, e.g. coated granules, impregnated granules and homogeneousgranules, can be prepared by binding the active substances to solidcarriers. Examples of solid carriers are mineral earths such as silicagels, silicates, talc, kaolin, attaclay, limestone, lime, chalk, bole,loess, clay, dolomite, diatomaceous earth, calcium sulfate, magnesiumsulfate, magnesium oxide, ground synthetic materials, fertilizers, suchas, e.g., ammonium sulfate, ammonium phosphate, ammonium nitrate, ureas,and products of vegetable origin, such as cereal meal, tree bark meal,wood meal and nutshell meal, cellulose powders and other solid carriers.

Examples for composition types include, but are not limited to: 1.Composition types for dilution with water, i) Water-soluble concentrates(SL, LS): 10 parts by weight of a compound of formula I according to theinvention are dissolved in 90 parts by weight of water or in awater-soluble solvent. As an alternative, wetting agents or otherauxiliaries are added. The active substance dissolves upon dilution withwater. In this way, a composition having a content of 10% by weight ofactive substance is obtained. ii) Dispersible concentrates (DC): 20parts by weight of a compound of formula I according to the inventionare dissolved in 70 parts by weight of cyclohexanone with addition of 10parts by weight of a dispersant, e.g. polyvinylpyrrolidone. Dilutionwith water gives a dispersion. The active substance content is 20% byweight. iii) Emulsifiable concentrates (EC): 15 parts by weight of acompound of formula I according to the invention are dissolved in 75parts by weight of xylene with addition of calciumdodecylbenzenesulfonate and castor oil ethoxylate (in each case 5 partsby weight). Dilution with water gives an emulsion. The composition hasan active substance content of 15% by weight. iv) Emulsions (EW, EO,ES): 25 parts by weight of a compound of formula I according to theinvention are dissolved in 35 parts by weight of xylene with addition ofcalcium dodecylbenzenesulfonate and castor oil ethoxylate (in each case5 parts by weight). This mixture is introduced into 30 parts by weightof water by means of an emulsifying machine (Ultraturrax) and made intoa homogeneous emulsion. Dilution with water gives an emulsion. Thecomposition has an active substance content of 25% by weight. v)Suspensions (SC, OD, FS): In an agitated ball mill, 20 parts by weightof a compound of formula I according to the invention are comminutedwith addition of 10 parts by weight of dispersants and wetting agentsand 70 parts by weight of water or an organic solvent to give a fineactive substance suspension. Dilution with water gives a stablesuspension of the active substance. The active substance content in thecomposition is 20% by weight. vi) Water-dispersible granules andwater-soluble granules (WG, SG) 50 parts by weight of a compound offormula I according to the invention are ground finely with addition of50 parts by weight of dispersants and wetting agents and prepared aswater-dispersible or water-soluble granules by means of technicalappliances (e.g. extrusion, spray tower, fluidized bed). Dilution withwater gives a stable dispersion or solution of the active substance. Thecomposition has an active substance content of 50% by weight. vii)Water-dispersible powders and water-soluble powders (WP, SP, SS, WS) 75parts by weight of a compound of formula I according to the inventionare ground in a rotor-stator mill with addition of 25 parts by weight ofdispersants, wetting agents and silica gel. Dilution with water gives astable dispersion or solution of the active substance. The activesubstance content of the composition is 75% by weight. viii) Gel (GF):In an agitated ball mill, 20 parts by weight of a compound of formula Iaccording to the invention are comminuted with addition of 10 parts byweight of dispersants, 1 part by weight of a gelling agent wetters and70 parts by weight of water or of an organic solvent to give a finesuspension of the active substance. Dilution with water gives a stablesuspension of the active substance, whereby a composition with 20% (w/w)of active substance is obtained.

2. Composition types to be applied undiluted: ix) Dustable powders (DP,DS): 5 parts by weight of a compound of formula I according to theinvention are ground finely and mixed intimately with 95 parts by weightof finely divided kaolin. This gives a dustable composition having anactive substance content of 5% by weight. x) Granules (GR, FG, GG, MG):0.5 parts by weight of a compound of formula I according to theinvention is ground finely and associated with 99.5 parts by weight ofcarriers. Current methods are extrusion, spray-drying or the fluidizedbed. This gives granules to be applied undiluted having an activesubstance content of 0.5% by weight. xi) ULV solutions (UL) 10 parts byweight of a compound of formula I according to the invention aredissolved in 90 parts by weight of an organic solvent, e.g. xylene. Thisgives a composition to be applied undiluted having an active substancecontent of 10% by weight.

The agrochemical compositions generally comprise between 0.01 and 95%,preferably between 0.1 and 90%, most preferably between 0.5 and 90%, byweight of active substance. The active substances are employed in apurity of from 90% to 100%, preferably from 95% to 100% (according toNMR spectrum).

Water-soluble concentrates (LS), flowable concentrates (FS), powders fordry treatment (DS), water-dispersible powders for slurry treatment (WS),water-soluble powders (SS), emulsions (ES) emulsifiable concentrates(EC) and gels (GF) are usually employed for the purposes of treatment ofplant propagation materials, particularly seeds. These compositions canbe applied to plant propagation materials, particularly seeds, dilutedor undiluted. The compositions in question give, after two-to-tenfolddilution, active substance concentrations of from 0.01 to 60% by weight,preferably from 0.1 to 40% by weight, in the ready-to-use preparations.Application can be carried out before or during sowing. Methods forapplying or treating agrochemical compounds and compositions thereof,respectively, on to plant propagation material, especially seeds, areknown in the art, and include dressing, coating, pelleting, dusting,soaking and in-furrow application methods of the propagation material.In a preferred embodiment, the compounds or the compositions thereof,respectively, are applied on to the plant propagation material by amethod such that germination is not induced, e.g. by seed dressing,pelleting, coating and dusting.

In a preferred embodiment, a suspension-type (FS) composition is usedfor seed treatment. Typically, a FS composition may comprise 1-800 g/lof active substance, 1-200 g/l Surfactant, 0 to 200 g/l antifreezingagent, 0 to 400 g/l of binder, 0 to 200 g/l of a pigment and up to 1liter of a solvent, preferably water.

The active substances can be used as such or in the form of theircompositions, e.g. in the form of directly sprayable solutions, powders,suspensions, dispersions, emulsions, dispersions, pastes, dustableproducts, materials for spreading, or granules, by means of spraying,atomizing, dusting, spreading, brushing, immersing or pouring. Theapplication forms depend entirely on the intended purposes; it isintended to ensure in each case the finest possible distribution of theactive substances according to the invention. Aqueous application formscan be prepared from emulsion concentrates, pastes or wettable powders(sprayable powders, oil dispersions) by adding water. To prepareemulsions, pastes or oil dispersions, the substances, as such ordissolved in an oil or solvent, can be homogenized in water by means ofa wetter, tackifier, dispersant or emulsifier. Alternatively, it ispossible to prepare concentrates composed of active substance, wetter,tackifier, dispersant or emulsifier and, if appropriate, solvent or oil,and such concentrates are suitable for dilution with water.

The active substance concentrations in the ready-to-use preparations canbe varied within relatively wide ranges. In general, they are from0.0001 to 10%, preferably from 0.001 to 1% by weight of activesubstance.

The active substances may also be used successfully in theultra-low-volume process (ULV), it being possible to apply compositionscomprising over 95% by weight of active substance, or even to apply theactive substance without additives.

When employed in plant protection, the amounts of active substancesapplied are, depending on the kind of effect desired, from 0.001 to 2 kgper ha, preferably from 0.005 to 2 kg per ha, more preferably from 0.05to 0.9 kg per ha, in particular from 0.1 to 0.75 kg per ha.

In treatment of plant propagation materials such as seeds, e.g. bydusting, coating or drenching seed, amounts of active substance of from0.1 to 1000 g, preferably from 1 to 1000 g, more preferably from 1 to100 g and most preferably from 5 to 100 g, per 100 kilogram of plantpropagation material (preferably seed) are generally required.

When used in the protection of materials or stored products, the amountof active substance applied depends on the kind of application area andon the desired effect. Amounts customarily applied in the protection ofmaterials are, e.g., 0.001 g to 2 kg, preferably 0.005 g to 1 kg, ofactive substance per cubic meter of treated material.

Various types of oils, wetters, adjuvants, herbicides, bactericides,other fungicides and/or pesticides may be added to the active substancesor the compositions comprising them, if appropriate not untilimmediately prior to use (tank mix). These agents can be admixed withthe compositions according to the invention in a weight ratio of 1:100to 100:1, preferably 1:10 to 10:1.

Adjuvants which can be used are in particular organic modifiedpolysiloxanes such as Break Thru S 240®; alcohol alkoxylates such asAtplus 245®, Atplus MBA 1303®, Plurafac LF 300® and Lutensol ON 30®;EO/PO block polymers, e.g. Pluronic RPE 2035® and Genapol B®; alcoholethoxylates such as Lutensol XP 80®; and dioctyl sulfosuccinate sodiumsuch as Leophen RA®.

The compositions according to the invention can, in the use form asfungicides, also be present together with other active substances, e.g.with herbicides, insecticides, growth regulators, fungicides or elsewith fertilizers, as pre-mix or, if appropriate, not until immediatelyprior to use (tank mix).

Mixing the compounds of formula I or the compositions comprising them inthe use form as fungicides with other fungicides results in many casesin an expansion of the fungicidal spectrum of activity being obtained orin a prevention of fungicide resistance development. Furthermore, inmany cases, synergistic effects are obtained.

The following list of active substances, in conjunction with which thecompounds according to the invention can be used, is intended toillustrate the possible combinations but does not limit them:

A) strobilurins azoxystrobin, dimoxystrobin, enestroburin,fluoxastrobin, kresoxim-methyl, meto-minostrobin, orysastrobin,picoxystrobin, pyraclostrobin, pyribencarb, trifloxystrobin,2-(2-(6-(3-chloro-2-methyl-phenoxy)-5-fluoro-pyrimidin-4-yloxy)-phenyl)-2-methoxyimino-N-methyl-acetamide,3-methoxy-2-(2-(N-(4-methoxy-phenyl)-cyclopropane-carboximidoylsulfanylmethyl)-phenyl)-acrylicacid methyl ester, methyl(2-chloro-5-[1-(3-methylbenzyloxyimino)ethyl]benzyl)carbamate and2-(2-(3-(2,6-dichlorophenyl)-1-methyl-allylideneaminooxymethyl)-phenyl)-2-methoxyimino-N-methyl-acetamide;

B) carboxamides and carboxanilides: benalaxyl, benalaxyl-M, benodanil,bixafen, boscalid, carboxin, fenfuram, fenhexamid, flutolanil,furametpyr, isopyrazam, isotianil, kiralaxyl, me-pronil, metalaxyl,metalaxyl-M (mefenoxam), ofurace, oxadixyl, oxycarboxin, pen-thiopyrad,sedaxane, tecloftalam, thifluzamide, tiadinil,2-amino-4-methyl-thiazole-5-carboxanilide,2-chloro-N-(1,1,3-trimethyl-indan-4-yl)-nicotinamide,N-(3′,4′,5′-trifluorobiphenyl-2-yl)-3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxamide,N-(4′-trifluoromethylthiobiphenyl-2-yl)-3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxamide,N-(2-(1,3-dimethyl-butyl)-phenyl)-1,3-dimethyl-5-fluoro-1H-pyrazole-4-carboxamideandN-(2-(1,3,3-trimethyl-butyl)-phenyl)-1,3-dimethyl-5-fluoro-1H-pyrazole-4-carboxamide;carboxylic morpholides: dimethomorph, flumorph, pyrimorph; benzoic acidamides: flumetover, fluopicolide, fluopyram, zoxamide,N-(3-Ethyl-3,5,5-trimethyl-cyclohexyl)-3-formylamino-2-hydroxy-benzamide;other carboxamides: carpropamid, dicyclomet, mandiproamid,oxytetracyclin, silthiofarm and N-(6-methoxy-pyridin-3-yl)cyclopropanecarboxylic acid amide;

C) azoles and triazoles: azaconazole, bitertanol, bromuconazole,cyproconazole, difenoconazole, diniconazole, diniconazole-M,epoxiconazole, fenbuconazole, fluquinconazole, flusilazole, flutriafol,hexaconazole, imibenconazole, ipconazole, metconazole, myclobutanil,oxpoconazole, paclobutrazole, penconazole, propiconazole,prothioconazole, simeconazole, tebuconazole, tetraconazole, triadimefon,triadimenol, triticonazole, uniconazole,1-(4-chloro-phenyl)-2-([1,2,4]triazol-1-yl)-cycloheptanol; imidazoles:cyazofamid, imazalil, pefurazoate, prochloraz, triflumizol;benzimidazoles: benomyl, carbendazim, fuberidazole, thiabendazole;—others: ethaboxam, etridiazole, hymexazole and2-(4-chloro-phenyl)-N-[4-(3,4-dimethoxy-phenyl)-isoxazol-5-yl]-2-prop-2-ynyloxy-acetamide;

D) heterocyclic compounds pyridines: fluazinam, pyrifenox,3-[5-(4-chloro-phenyl)-2,3-dimethyl-isoxazolidin-3-yl]-pyridine,3-[5-(4-methyl-phenyl)-2,3-dimethyl-isoxazolidin-3-yl]-pyridine,2,3,5,6-tetra-chloro-4-methanesulfonyl-pyridine,3,4,5-trichloropyridine-2,6-di-carbonitrile,N-(1-(5-bromo-3-chloro-pyridin-2-yl)-ethyl)-2,4-dichloronicotinamide,N-[(5-bromo-3-chloro-pyridin-2-yl)-methyl]-2,4-dichloro-nicotinamide;pyrimidines: bupirimate, cyprodinil, diflumetorim, fenarimol, ferimzone,mepanipyrim, nitrapyrin, nuarimol, pyrimethanil; piperazines: triforine;pyrroles: fenpiclonil, fludioxonil; morpholines: aldimorph, dodemorph,dodemorph-acetate, fenpropimorph, tridemorph; piperidines: fenpropidin;—dicarboximides: fluoroimid, iprodione, procymidone, vinclozolin;non-aromatic 5-membered heterocycles: famoxadone, fenamidone, flutianil,octhilinone, probenazole,5-amino-2-isopropyl-3-oxo-4-ortho-tolyl-2,3-dihydro-pyrazole-1-carbothioicacid S-allyl ester; others: acibenzolar-S-methyl, amisulbrom, anilazin,blasticidin-S, captafol, captan, chinomethionat, dazomet, debacarb,diclomezine, difenzoquat, difenzoquat-methylsulfate, fenoxanil, Folpet,oxolinic acid, piperalin, proquinazid, pyroquilon, quinoxyfen,triazoxide, tricyclazole, 2-butoxy-6-iodo-3-propylchromen-4-one,5-chloro-1-(4,6-dimethoxy-pyrimidin-2-yl)-2-methyl-1H-benzimidazole,5-chloro-7-(4-methylpiperidin-1-yl)-6-(2,4,6-trifluorophenyl)-[1,2,4]triazolo[1,5-a]pyrimidineand 5-ethyl-6-octyl-[1,2,4]triazolo[1,5-a]pyrimidine-7-ylamine;

E) carbamates thio- and dithiocarbamates: ferbam, mancozeb, maneb,metam, methasulphocarb, metiram, propineb, thiram, zineb, ziram;carbamates: benthiavalicarb, diethofencarb, iprovalicarb, propamocarb,propamo-carb hydrochlorid, valiphenal andN-(1-(1-(4-cyano-phenyl)ethanesulfonyl)-but-2-yl) carbamicacid-(4-fluorophenyl) ester;

F) other active substances—guanidines: guanidine, dodine, dodine freebase, guazatine, guazatine-acetate, iminoctadine,iminoctadine-triacetate, iminoctadine-tris(albesilate); antibiotics:kasugamycin, kasugamycin hydrochloride-hydrate, streptomycin,pol-yoxine, validamycin A; nitrophenyl derivates: binapacryl, dinobuton,dinocap, nitrthal-isopropyl, tecna-zen, organometal compounds: fentinsalts, such as fentin-acetate, fentin chloride or fentin hydroxide;sulfur-containing heterocyclyl compounds: dithianon, isoprothiolane;organophosphorus compounds: edifenphos, fosetyl, fosetyl-aluminum,iproben-fos, phosphorous acid and its salts, pyrazophos,tolclofos-methyl; organochlorine compounds: chlorothalonil,dichlofluanid, dichlorophen, flusulfamide, hexachlorobenzene,pencycuron, pentachlorphenole and its salts, phthalide, quintozene,thiophanate-methyl, tolylfluanid,N-(4-chloro-2-nitro-phenyl)-N-ethyl-4-methyl-benzenesulfonamide;inorganic active substances: Bordeaux mixture, copper acetate, copperhydroxide, copper oxychloride, basic copper sulfate, sulfur; biphenyl,bronopol, cyflufenamid, cymoxanil, diphenylamin, metrafenone,mildiomycin, oxin-copper, prohexadione-calcium, spiroxamine,tolylfluanid,N-(cyclopropylmethoxyimino-(6-difluoro-methoxy-2,3-difluoro-phenyl)-methyl)-2-phenylacetamide,N′-(4-(4-chloro-3-trifluoromethyl-phenoxy)-2,5-dimethyl-phenyl)-N-ethyl-N-methylformamidine,N′-(4-(4-fluoro-3-trifluoromethyl-phenoxy)-2,5-dimethyl-phenyl)-N-ethyl-N-methylformamidine,N′-(2-methyl-5-trifluoromethyl-4-(3-trimethylsilanyl-propoxy)-phenyl)-N-ethyl-N-methylformamidine,N′-(5-difluoromethyl-2-methyl-4-(3-trimethylsilanyl-propoxy)-phenyl)-N-ethyl-N-methylformamidine,2-{1-[2-(5-methyl-3-trifluoromethyl-pyrazole-1-yl)-acetyl]-piperidin-4-yl}-thiazole-4-carboxylicacid methyl-(1,2,3,4-tetrahydro-naphthalen-1-yl)-amide,2-{1-[2-(5-methyl-S-trifluoromethyl-pyrazole-i-yO-acety^-piperidin^-ylJ-thiazole^-carboxylicacid methyl-(R)-1,2,3,4-tetrahydro-naphthalen-1-yl-amide, acetic acid6-tert-butyl-8-fluoro-2,3-dimethyl-quinolin-4-yl ester andmethoxy-acetic acid 6-tert-butyl-8-fluoro-2,3-dimethyl-quinolin-4-ylester.

G) growth regulators abscisic acid, amidochlor, ancymidol,6-benzylaminopurine, brassinolide, butralin, chlormequat (chlormequatchloride), choline chloride, cyclanilide, daminozide, dikegulac,dimethipin, 2,6-dimethylpuridine, ethephon, flumetralin, flurprimidol,fluthiacet, forchlorfenuron, gibberellic acid, inabenfide,indole-3-acetic acid, maleic hydrazide, mefluidide, mepiquat (mepiquatchloride), naphthaleneacetic acid, N-6-benzyladenine, paclobutrazol,prohexadione (prohexadione-calcium), prohydrojasmon, thidiazuron,triapenthenol, tributyl phosphorotrithioate, 2,3,5-tri-iodobenzoic acid,trinexapac-ethyl and uniconazole;

H) herbicides acetamides: acetochlor, alachlor, butachlor, dimethachlor,dimethenamid, flufen-acet, mefenacet, metolachlor, metazachlor,napropamide, naproanilide, pethox-amid, pretilachlor, propachlor,thenylchlor; amino acid derivatives: bilanafos, glyphosate, glufosinate,sulfosate; aryloxyphenoxypropionates: clodinafop, cyhalofop-butyl,fenoxaprop, fluazifop, haloxyfop, metamifop, propaquizafop, quizalofop,quizalofop-P-tefuryl; Bipyridyls: diquat, paraquat; (thio)carbamates:asulam, butylate, carbetamide, desmedipham, dimepiperate, eptam (EPTC),esprocarb, molinate, orbencarb, phenmedipham, prosulfocarb,pyributicarb, thiobencarb, triallate; cyclohexanediones: butroxydim,clethodim, cycloxydim, profoxydim, sethoxydim, tepraloxydim,tralkoxydim; —dinitroanilines: benfluralin, ethalfluralin, oryzalin,pendimethalin, prodiamine, trifluralin; diphenyl ethers: acifluorfen,aclonifen, bifenox, diclofop, ethoxyfen, fomesafen, lactofen,oxyfluorfen; hydroxybenzonitriles: bomoxynil, dichlobenil, ioxynil;—imidazolinones: imazamethabenz, imazamox, imazapic, imazapyr,imazaquin, imazethapyr; phenoxy acetic acids: clomeprop,2,4-dichlorophenoxyacetic acid (2,4-D), 2,4-DB, dichlorprop, MCPA,MCPA-thioethyl, MCPB, Mecoprop; pyrazines: chloridazon, flufenpyr-ethyl,fluthiacet, norflurazon, pyridate; pyridines: aminopyralid, clopyralid,diflufenican, dithiopyr, fluridone, fluroxypyr, picloram, picolinafen,thiazopyr; sulfonyl ureas: amidosulfuron, azimsulfuron, bensulfuron,chlorimuron-ethyl, chlorsulfuron, cinosulfuron, cyclosulfamuron,ethoxysulfuron, flazasulfuron, flucetosulfuron, flupyrsulfuron,foramsulfuron, halosulfuron, imazosulfuron, iodosulfu-ron, mesosulfuron,metsulfuron-methyl, nicosulfuron, oxasulfuron, primisulfuron,prosulfuron, pyrazosulfuron, rimsulfuron, sulfometuron, sulfosulfuron,thifensulfuron, triasulfuron, tribenuron, trifloxysulfuron,triflusulfuron, tritosulfuron,1-((2-chloro-6-propyl-imidazo[1,2-b]pyridazin-3-yl)sulfonyl)-3-(4,6-dimethoxy-pyrmidin-2-yl)urea;triazines: ametryn, atrazine, cyanazine, dimethametryn, ethiozin,hexazinone, metamitron, metribuzin, prometryn, simazine, terbuthylazine,terbutryn, triaziflam; ureas: chlorotoluron, daimuron, diuron,fluometuron, isoproturon, linuron, metha-benzthiazuron, tebuthiuron;other acetolactate synthase inhibitors: bispyribac-sodium,cloransulam-methyl, diclosulam, florasulam, flucarbazone, flumetsulam,metosulam, ortho-sulfamuron, penoxsulam, propoxycarbazone,pyribambenz-propyl, pyribenzoxim, pyriftalid, pyriminobac-methyl,pyrimisulfan, pyrithiobac, pyroxasulfone, pyroxsulam; others:amicarbazone, aminotriazole, anilofos, beflubutamid, benazolin,bencar-bazone, benfluresate, benzofenap, bentazone, benzobicyclon,bromacil, bromo-butide, butafenacil, butamifos, cafenstrole,carfentrazone, cinidon-ethlyl, chlor-thal, cinmethylin, clomazone,cumyluron, cyprosulfamide, dicamba, difenzoquat, diflufenzopyr,Drechslera monoceras, endothal, ethofumesate, etobenzanid,fen-trazamide, flumiclorac-pentyl, flumioxazin, flupoxam,flurochloridone, flurtamone, indanofan, isoxaben, isoxaflutole, lenacil,propanil, propyzamide, quinclorac, quinmerac, mesotrione, methyl arsonicacid, naptalam, oxadiargyl, oxadiazon, oxaziclomefone, pentoxazone,pinoxaden, pyraclonil, pyraflufen-ethyl, pyrasulfo-tole, pyrazoxyfen,pyrazolynate, quinoclamine, saflufenacil, sulcotrione, sulfentra-zone,terbacil, tefuryltrione, tembotrione, thiencarbazone, topramezone,4-hydroxy-3-[2-(2-methoxy-ethoxymethyl)-6-trifluoromethyl-pyridine-3-carbonyl]-bicyclo[3.2.1]oct-3-en-2-one,(3-[2-chloro-4-fluoro-5-(3-methyl-2,6-dioxo-4-trifluoromethyl-3,6-dihydro-2H-pyrimidin-1-yl)-phenoxy]-pyridin-2-yloxy)-aceticacid ethyl ester, 6-amino-5-chloro-2-cyclopropyl-pyrimidine-4-carboxylicacid methyl ester,6-chloro-3-(2-cyclopropyl-6-methyl-phenoxy)-pyridazin-4-ol,4-amino-3-chloro-6-(4-chloro-phenyl)-5-fluoro-pyridine-2-carboxylicacid,4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxy-phenyl)-pyridine-2-carboxylicacid methyl ester, and4-amino-3-chloro-6-(4-chloro-3-dimethylamino-2-fluoro-phenyl)-pyridine-2-carboxylicacid methyl ester.

I) insecticides—organo(thio)phosphates: acephate, azamethiphos,azinphos-methyl, chlorpyrifos, chlorpyrifos-methyl, chlorfenvinphos,diazinon, dichlorvos, dicrotophos, dimethoate, disulfoton, ethion,fenitrothion, fenthion, isoxathion, malathion, methamido-phos,methidathion, methyl-parathion, mevinphos, monocrotophos,oxydemeton-methyl, paraoxon, parathion, phenthoate, phosalone, phosmet,phosphamidon, phorate, phoxim, pirimiphos-methyl, profenofos,prothiofos, sulprophos, tetra-chlorvinphos, terbufos, triazophos,trichlorfon; carbamates: alanycarb, aldicarb, bendiocarb, benfuracarb,carbaryl, carbofuran, carbosulfan, fenoxycarb, furathiocarb, methiocarb,methomyl, oxamyl, pirimicarb, propoxur, thiodicarb, triazamate;pyrethroids: allethrin, bifenthrin, cyfluthrin, cyhalothrin,cyphenothrin, cypermethrin, alpha-cypermethrin, beta-cypermethrin,zeta-cypermethrin, deltamethrin, esfenvalerate, etofenprox,fenpropathrin, fenvalerate, imiprothrin, lambda-cyhalothrin, permethrin,prallethrin, pyrethrin I and II, resmethrin, silafluofen,tau-fluvalinate, tefluthrin, tetramethrin, tralomethrin, transfluthrin,profluthrin, dimefluthrin; insect growth regulators: a) chitin synthesisinhibitors: benzoylureas: chlorfluazuron, cyramazin, diflubenzuron,flucycloxuron, flufenoxuron, hexaflumuron, lufenuron, novaluron,teflubenzuron, triflumuron; buprofezin, diofenolan, hexythiazox,etoxazole, clofentazine; b) ecdysone antagonists: halofenozide,methoxyfenozide, tebufenozide, azadirachtin; c) juvenoids: pyriproxyfen,methoprene, fenoxycarb; d) lipid biosynthesis inhibitors: spirodiclofen,spiromesifen, spirotetramat; nicotinic receptor agonists/antagonistscompounds: clothianidin, dinotefuran, imi-dacloprid, thiamethoxam,nitenpyram, acetamiprid, thiacloprid,1-(2-chloro-thiazol-5-ylmethyl)-2-nitrimino-3,5-dimethyl-[1,3,5]triazinane;GABA antagonist compounds: endosulfan, ethiprole, fipronil, vaniliprole,pyrafluprole, pyriprole,5-amino-1-(2,6-dichloro-4-methyl-phenyl)-4-sulfinamoyl-1H-pyrazole-3-carbothioicacid amide; macrocyclic lactone insecticides: abamectin, emamectin,milbemectin, lepimectin, spinosad, spinetoram; mitochondrial electrontransport inhibitor (METI) I acaricides: fenazaquin, pyrida-ben,tebufenpyrad, tolfenpyrad, flufenerim; METI Il and III compounds:acequinocyl, fluacyprim, hydramethylnon; Uncouplers: chlorfenapyr;—oxidative phosphorylation inhibitors: cyhexatin, diafenthiuron,fenbutatin oxide, propargite; moulting disruptor compounds: cryomazine;mixed function oxidase inhibitors: piperonyl butoxide; sodium channelblockers: indoxacarb, metaflumizone; —others: benclothiaz, bifenazate,cartap, flonicamid, pyridalyl, pymetrozine, sulfur, thiocyclam,flubendiamide, chlorantraniliprole, cyazypyr (HGW86), cyenopyrafen,flupyrazofos, cyflumetofen, amidoflumet, imicyafos, bistrifluron, andpyrifluquinazon.

The present invention furthermore relates to agrochemical compositionscomprising a mixture of at least one compound of formula I (component 1)and at least one further active substance useful for plant protection,e.g. selected from the groups A) to I) (component 2), in particular onefurther fungicide, e.g. one or more fungicide from the groups A) to F),as described above, and if desired one suitable solvent or solidcarrier. Those mixtures are of particular interest, since many of themat the same application rate show higher efficiencies against harmfulfungi. Furthermore, combating harmful fungi with a mixture of compoundsof formula I and at least one fungicide from groups A) to F), asdescribed above, is more efficient than combating those fungi withindividual compounds of formula I or individual fungicides from groupsA) to F). By applying compounds of formula I together with at least oneactive substance from groups A) to I) a synergistic effect can beobtained, i.e. more than simple addition of the individual effects isobtained (synergistic mixtures).

According to this invention, applying the compounds of formula Itogether with at least one further active substance is to be understoodto denote that at least one compound of formula I and at least onefurther active substance occur simultaneously at the site of action(i.e. the harmful fungi to be controlled or their habitats such asinfected plants, plant propagation materials, particularly seeds,surfaces, materials or the soil as well as plants, plant propagationmaterials, particularly seeds, soil, surfaces, materials or rooms to beprotected from fungal attack) in a fungicidally effective amount. Thiscan be obtained by applying the compounds of formula I and at least onefurther active substance simultaneously, either jointly (e.g. astankmix) or separately, or in succession, wherein the time intervalbetween the individual applications is selected to ensure that theactive substance applied first still occurs at the site of action in asufficient amount at the time of application of the further activesubstance(s). The order of application is not essential for working ofthe present invention.

In binary mixtures, i.e. compositions according to the inventioncomprising one compound I (component 1) and one further active substance(component 2), e.g. one active substance from groups A) to I), theweight ratio of component 1 and component 2 generally depends from theproperties of the active substances used, usually it is in the range offrom 1:100 to 100:1, regularly in the range of from 1:50 to 50:1,preferably in the range of from 1:20 to 20:1, more preferably in therange of from 1:10 to 10:1 and in particular in the range of from 1:3 to3:1.

In ternary mixtures, i.e. compositions according to the inventioncomprising one compound I (component 1) and a first further activesubstance (component 2) and a second further active substance (component3), e.g. two active substances from groups A) to I), the weight ratio ofcomponent 1 and component 2 depends from the properties of the activesubstances used, preferably it is in the range of from 1:50 to 50:1 andparticularly in the range of from 1:10 to 10:1, and the weight ratio ofcomponent 1 and component 3 preferably is in the range of from 1:50 to50:1 and particularly in the range of from 1:10 to 10:1.

The components can be used individually or already partially orcompletely mixed with one another to prepare the composition accordingto the invention. It is also possible for them to be packaged and usedfurther as combination composition such as a kit of parts.

In one embodiment of the invention, the kits may include one or more,including all, components that may be used to prepare a subjectagrochemical composition. E. g., kits may include one or more fungicidecomponent(s) and/or an adjuvant component and/or an insecticidecomponent and/or a growth regulator component and/or a herbicide. One ormore of the components may already be combined together orpre-formulated. In those embodiments where more than two components areprovided in a kit, the components may already be combined together andas such are packaged in a single container such as a vial, bottle, can,pouch, bag or canister. In other embodiments, two or more components ofa kit may be packaged separately, i.e., not pre-formulated. As such,kits may include one or more separate containers such as vials, cans,bottles, pouches, bags or canisters, each container containing aseparate component for an agrochemical composition. In both forms, acomponent of the kit may be applied separately from or together with thefurther components or as a component of a combination compositionaccording to the invention for preparing the composition according tothe invention.

The user applies the composition according to the invention usually froma predosage device, a knapsack sprayer, a spray tank or a spray plane.Here, the agrochemical composition is made up with water and/or bufferto the desired application concentration, it being possible, ifappropriate, to add further auxiliaries, and the ready-to-use sprayliquor or the agrochemical composition according to the invention isthus obtained. In some embodiments, 50 to 500 liters of the ready-to-usespray liquor are applied per hectare of agricultural useful area. Insome embodiments 100 to 400 liters of the ready-to-use spray liquor areapplied per hectare. In some embodiments, the invention provides a kitfor greenhouse application of a ready-to-use composition of theinvention.

According to one embodiment, individual components of the compositionaccording to the invention such as parts of a kit or parts of a binaryor ternary mixture may be mixed by the user himself in a spray tank andfurther auxiliaries may be added, if appropriate (tank mix). In afurther embodiment, either individual components of the compositionaccording to the invention or partially premixed components, e.g.components comprising compounds of formula I and/or active substancesfrom the groups A) to I), may be mixed by the user in a spray tank andfurther auxiliaries and additives may be added, if appropriate (tankmix).

In a further embodiment, either individual components of the compositionaccording to the invention or partially premixed components, e.g.components comprising compounds of formula I and/or active substancesfrom the groups A) to I), can be applied jointly (e.g. after tankmix) orconsecutively.

In some embodiments the invention provides a mixture comprising acompound of formula I (component 1) and at least one active substanceselected from the strobilurines of group A) (component 2) andparticularly selected from azoxystrobin, dimoxystrobin, fluoxastrobin,kresoxim-methyl, orysastrobin, picoxystrobin, pyraclostrobin andtrifloxystrobin.

In some embodiments the invention provides a mixture comprising acompound of formula I (component 1) and at least one active substanceselected from the carboxamides of group B) (component 2). In someembodiments, the carboxamide is selected from the group consisting ofbixafen, boscalid, sedaxane, fenhexamid, metalaxyl, isopyrazam,mefenoxam, ofurace, dimethomorph, flumorph, fluopicolid (picobenzamid),zoxamide, carpropamid, mandipropamid andN-(3′,4′,5′-trifluorobiphenyl-2-yl)-3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxamide.

In some embodiments the invention provides a mixture comprising acompound of formula I (component 1) and at least one active substanceselected from the azoles of group C) (component 2). In some embodiments,the azole is selected from the group consisting of cyproconazole,difenoconazole, epoxicona-zole, fluquinconazole, flusilazole,flutriafol, metconazole, myclobutanil, penconazole, propiconazole,prothioconazole, triadimefon, triadimenol, tebuconazole, tetraconazole,triticonazole, prochloraz, cyazofamid, benomyl, carbendazim andethaboxam.

In some embodiments the invention provides a mixture comprising acompound of formula I (component 1) and at least one active substanceselected from the heterocyclic compounds of group D) (component 2). Insome embodiments, the heterocyclic compounds of group D) are selectedfrom the group consisting of fluazinam, cyprodinil, fenarimol,mepanipyrim, pyrimethanil, triforine, fludioxonil, dodemorph,fenpropimorph, tridemorph, fenpropidin, iprodione, vinclozolin,famoxadone, fenamidone, probenazole, proquinazid, acibenzolar-S-methyl,captafol, folpet, fenoxanil, quinoxyfen and5-ethyl-6-octyl-[1,2,4]triazolo[1,5-a]pyrimidine-7-ylamine.

In some embodiments the invention provides a mixture comprising acompound of formula I (component 1) and at least one active substanceselected from the carbamates of group E) (component 2). In someembodiments, the carbamates are selected from the group consisting ofmancozeb, metiram, propineb, thiram, iprovalicarb, benthiavalicarb andpropamocarb.

In some embodiments the invention provides a mixture comprising acompound of formula I (component 1) and at least one active substanceselected from the fungicides given in group F) (component 2). In someembodiments, the fungicides of group F) are selected from the groupconsisting of dithianon, fentin salts, such as fentin acetate, fosetyl,fosetyl-aluminium, H3PO3 and salts thereof, chlorthalonil,dichlofluanid, thiophanat-methyl, copper acetate, copper hydroxide,copper oxychloride, copper sulfate, sulfur, cymoxanil, metrafenone andspiroxamine.

The active substances referred to as component 2, their preparation andtheir activity against harmful fungi is known in the art. In someembodiments these substances are commercially available. The compoundsdescribed by IUPAC nomenclature, their preparation and their fungicidalactivity are also known in the art (cf. Can. J. Plant Sci. 48(6),587-94, 1968; EP-A 141 317; EP-A 152 031; EP-A 226 917; EP-A 243 970;EP-A 256 503; EP-A 428 941; EP-A 532 022; EP-A 1 028 125; EP-A 1 035122; EP-A 1 201 648; EP-A 1 122 244, JP 2002316902; DE 19650197; DE10021412; DE 102005009458; U.S. Pat. Nos. 3,296,272; 3,325,503; WO98/46608; WO 99/14187; WO 99/24413; WO 99/27783; WO 00/29404; WO00/46148; WO 00/65913; WO 01/54501; WO 01/56358; WO 02/22583; WO02/40431; WO 03/10149; WO 03/1 1853; WO 03/14103; WO 03/16286; WO03/53145; WO 03/61388; WO 03/66609; WO 03/74491; WO 04/49804; WO04/83193; WO 05/120234; WO 05/123689; WO 05/123690; WO 05/63721; WO05/87772; WO 05/87773; WO 06/15866; WO 06/87325; WO 06/87343; WO07/82098; WO 07/90624).

The mixtures of active substances can be prepared as compositionscomprising besides the active ingredients at least one inert ingredientby usual means, e.g. by the means given for the compositions ofcompounds of formula I.

Concerning usual ingredients of such compositions reference is made tothe explanations given for the compositions containing compounds offormula I.

The mixtures of active substances according to the present invention aresuitable as fungicides, as are the compounds of formula I. In someembodiments the mixtures and compositions of the present invention areuseful for the protection of plants against a broad spectrum ofphytopathogenic fungi. In some embodiments, the phytopathogenic fungiare from the classes of the Ascomycetes, Basidiomycetes, Deuteromycetesand Peronosporomycetes (syn. Oomycetes).

The compounds of formula I and pharmaceutically acceptable salts thereofare also suitable for treating diseases in men and animals, especiallyas antimycotics, for treating cancer and for treating virus infections.The term “antimycotic”, as distinguished from the term “fungicide”,refers to a medicament for combating zoopathogenic or humanpathogenicfungi, i.e. for combating fungi in animals, especially in mammals(including humans) and birds.

In some embodiments, the present invention provides a medicamentcomprising at least one compound of formula I or a pharmaceuticallyacceptable salt thereof and a pharmaceutically acceptable carrier.

In some embodiments, the invention relates to the use of a compound offormula I or a pharmaceutically acceptable salt thereof for preparing anantimycotic medicament; i.e. for preparing a medicament for thetreatment and/or prophylaxis of infections with humanpathogenic and/orzoopathogenic fungi.

EXEMPLIFICATION

As depicted in the Examples below, in certain exemplary embodiments,compounds are prepared according to the following general procedures. Itwill be appreciated that, although the general methods depict thesynthesis of certain compounds of the present invention, the followinggeneral methods, and other methods known to one of ordinary skill in theart, can be applied to all compounds and subclasses and species of eachof these compounds, as described herein.

In certain embodiments, compounds of the present invention are generallyprepared according to Scheme I set forth below:

In Scheme I above, each instance of LG is a leaving group, PG is aprotecting group, and each of R¹, R², R³, R⁴, R^(A4), L¹, L², Q, X and Yis as defined above and below and in classes and subclasses as describedherein. Suitable leaving groups, LG, include but are not limited tohydroxyls, halogens and sulfonates. In certain embodiments, LG is ahalogen. In certain embodiments, LG is hydroxyl. In certain embodiments,LG is chlorine.

In one aspect, the present invention provides methods for preparingcompounds of formula E-2 according to the steps depicted in Scheme I,above. In some embodiments, step S-1 comprises treating a heterocyclicaminoester of formula E-1, of which many are commercially available,with a reagent for the protection of the amine moiety to form compoundsof formula E-2. In some embodiments the reagent is di-tert-butyldicarbonate. In some embodiments a catalyst is added. In someembodiments the catalyst is DMAP. In some embodiments the solvent isacetonitrile. In some embodiments, R^(A4) is C₁-C₄ alkyl. In someembodiments, R^(A4) is methyl, ethyl or propyl.

In some embodiments step S-2 comprises treating a compound of formulaE-2 with an aqueous base to form a carboxylic acid of formula E-3. Insome embodiments the base is lithium hydroxide. In some embodiments stepS-2 is performed in a solvent. In some embodiments the solvent is amixture of THF and water.

In some embodiments, at step S-3, a heterocyclic carboxylic acid offormula E-3 is reacted with an amine to form an amide of formula E-4. Incertain embodiments, the acylation reaction is performed in the presenceof an amine. In some embodiments the base is TEA. In some embodimentsthe reaction is performed in the presence of a coupling agent. In someembodiments the coupling reagent is HATU. In some embodiments thecoupling reagent is EDC. In some embodiments the reaction is performedwith both EDC and an additive. In some embodiments the additive is HOBT.In some embodiments the solvent is DMF.

In some embodiments step S-4 comprises treating a compound of formulaE-4 with a reagent for the removal of PG to from a compound of formulaE-5. In some embodiments, as for example when PG is atert-butoxycarbonyl group, the reagent is trifluoroacetic acid. In someembodiments, when the reagent is trifluoroacetic acid the solvent isDCM. In some embodiments, where PG is a hydrogenolytically removablegroup such as benzyl or benzhydryl, the reagent is hydrogen and aplatinum, nickel or palladium catalyst, and the solvent is an alcohol orester solvent such as ethanol or ethyl acetate.

In some embodiments step S-5 comprises treating a compound of formulaE-5 with a sulfonylating, carbonylating or thiocarbonylating reagent. Insome embodiments the sulfonylating reagent is sulfonyl chloride. In someembodiments the carbonylating reagent is phosgene. In some embodimentsthe thiocarbonylating reagent is thiophosgene. In some embodiments thereaction is performed in the presence of a base. In some embodiments thebase is TEA. In some embodiments the solvent is DCM. In some embodimentsthe solvent is toluene.

In some embodiments step S-6 comprises treating a compound of formulaE-6 with a base and an alkylating agent to form a compound of formulaE-7. In some embodiments the base is sodium hydride. In some embodimentsthe alkylating agent is an alkyl halide. In some embodiments thealkylating agent is an alkyl sulfonate. In some embodiments the solventis THF.

In certain embodiments, compounds of the present invention are generallyprepared according to Scheme II set forth below:

In Scheme II above, each of Hal, R¹, R², R³, R⁴, R^(A5), L¹, L², X and Yis as defined above and below and in classes and subclasses as describedherein.

In one aspect, the present invention provides methods for preparingcompounds of formula F-5 according to the steps depicted in Scheme II,above. In some embodiments, step S-1 comprises treating a heteroarylhalide of formula F-1, of which many are commercially avaialable, with acatalyst and a tin reagent to form stannane F-2. In some embodiments thecatalyst is a palladium complex. In some embodiments the tin reagent ishexamethylditin. In some embodiments the solvent is dimethoxyethane. Insome embodiments, R^(A5) is C₁-C₄ alkyl. In some embodiments, R^(A5) ismethyl, ethyl or propyl. In some embodiments, Hal is a halogen. In someembodiments, Hal is chlorine, bromine, or iodine.

In some embodiments step S-2 comprises treating a compound of formulaF-2 with a catalyst and an acid chloride to form ketoester F-3. In someembodiments the catalyst is a palladium complex. In some embodiments thesolvent is THF.

In some embodiments step S-3 comprises treating a compound of formulaF-3 with a hydrazine to form a compound of formula F-4. In someembodiments the solvent is methylene chloride. In some embodiments thereaction is performed in the presence of a desiccant. In someembodiments the desiccant is magnesium sulfate.

In some embodiments step S-4 comprises cyclizing a compound of formulaF-4 to form a compound of formula F-5. In some embodiments a catalyst isadded. In some embodiments the catalyst is p-toluenesulfonic acid. Insome embodiments the solvent is toluene.

In certain embodiments, compounds of the present invention are generallyprepared according to Scheme III set forth below:

In Scheme III above, each of Hal, R¹, R², R³, R⁴, R^(A6), L¹, L², X andY is as defined above and below and in classes and subclasses asdescribed herein.

In one aspect, the present invention provides methods for preparingcompounds of formula G-6 according to the steps depicted in Scheme III,above. In some embodiments, step S-1 comprises treating a heteroarylhalide of formula G-1, of which several are commercially available, witha catalyst and a tin reagent to form stannane G-2. In some embodimentsthe catalyst is a palladium complex. In some embodiments the tin reagentis hexamethylditin. In some embodiments the solvent is dimethoxyethane.In some embodiments, R^(A6) is C₁-C₄ alkyl. In some embodiments, R^(A6)is methyl, ethyl or propyl.

In some embodiments step S-2 comprises treating a compound of formulaG-2 with a catalyst and an acid chloride to form ketoester G-3. In someembodiments the catalyst is a palladium complex. In some embodiments thesolvent is THF.

In some embodiments step S-3 comprises treating a compound of formulaG-3 with chlorination reagents to form a compound of formula G-4. Insome embodiments the solvent is methylene chloride. In some embodimentsthe chlorination reagents are chlorosulfuric acid and thionyl chloride(see for example N. X. Yu et al. J. Labelled Comp. Radiopharm. 2004,27(2), 115-125.

In some embodiments step S-4 comprises condensing a compound of formulaG-4 with hydrazine hydrate to form a compound of formula G-5. In someembodiments the reaction is performed in the presence of an acid. Insome embodiments the catalyst is acetic acid. In some embodiments thesolvent is methanol.

In some embodiments step S-5 comprises treating a compound of formulaG-5 with base and an alkylating reagent to form a compound of formulaG-6. In some embodiments the base is sodium hydroxide. In someembodiments the alkylating agent is an alkyl halide. In some embodimentsa phase transfer catalyst is added (for example H. He et al. Org. Lett.2008, 10(12), 2421-2424).

Additional compounds of formula I were prepared in a mannersubstantially similar to that described above.

In certain embodiments, compounds of the present invention are assayedas inhibitors of ACC using methods known in the art including thosecontained in Harwood et al. Isozyme-nonselective N-SubstitutedBipiperidylcarboxamide Acetyl-CoA Carboxylase Inhibitors Reduce TissueMalonyl-CoA Concentrations, Inhibit Fatty Acid Synthesis, and IncreaseFatty Acid Oxidation in Cultured Cells and in Experimental Animals, J.Biol. Chem., 2003, vol. 278, 37099-37111. In some embodiments the assaysused are selected from an in vitro ACC enzyme inhibition assays, invitro cell culture assays, and in vivo efficacy assays in animals. Insome embodiments, assay results for compounds of the present inventionare compared to results obtained for known inhibitors of ACC or relatedenzymes. In some embodiments, the ACC inhibitor used for comparison isCP-640186 or soraphen A.

Compounds of the present invention are evaluated in an in vitro ACCinhibition assay as described by Harwood, et al, 2003, the entirety ofwhich is incorporated herein by reference.

Example 1 Synthesis of2-(4-((R)-2-(5-fluoro-2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-7-methyl-6-(oxazol-2-yl)-1,1-dioxido-3-oxo-3,4,4a,7a-tetra-hydro-2H-thieno[2,3-e][1,2,4]thiadiazin-2-yl)aceticacid, I-41

Synthesis of compound 1.2. A 250-mL round-bottom flask was charged withacetic acid (100 mL) and HNO₃ (4 g) followed by a dropwise addition of asolution of compound 1.1 (10 g, 56.48 mmol, 1.00 equiv) in Ac₂O (14 mL).Reaction was stirred overnight at 25° C. Upon completion, reaction wasquenched by the addition of 400 mL of water/ice. The solids werecollected by filtration to provide 11 g (88%) of compound 1.2 as ayellow solid.

Synthesis of compound 1.3. Into a 25-mL round-bottom flask, were placedcompound 1.2 (11 g, 49.54 mmol, 1.00 equiv), ethanol (110 mL), potassiumcarbonate (6.8 g, 49.20 mmol, 1.04 equiv), H₂O (25 mL), and solution ofBnSH (6.1 g) in ethanol (10 mL). The resulting solution was stirred for4 h at room temperature. The resulting mixture was concentrated undervacuum. The crude was purified using flash column chromatography tofurnish 3.0 g (25%) of compound 1.3 as a yellow solid.

Synthesis of compound 1.4. A 100-mL round bottom, was charged withcompound 1.3 (3.3 g, 12.44 mmol, 1.00 equiv), CH₃CN (46 mL), water (12mL), acetic acid (6 mL), followed by1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (7.3 g, 37.05 mmol,2.98 equiv). Reaction was stirred for 3 hours at room temperature. Uponcompletion solvents were removed under vacuum and resulting crude waspurified via flash column chromatography to furnish 2.2 g (73%) ofcompound 1.4 as a yellow solid.

Synthesis of compound 1.5. Into a 100-mL 3-necked round-bottom flask,were placed compound 1.4 (2.2 g, 9.10 mmol, 1.00 equiv), dichloromethane(30 mL), 2-[(2-aminoacetyl)oxy]-2-methylpropyl (1.5 g, 11.52 mmol, 1.27equiv), and Et₃N (1.84 g, 18.18 mmol, 2.00 equiv). Reaction was stirredfor 1 hour at room temperature. The resulting mixture was concentratedunder vacuum. The crude was purified using flash column chromatographyto furnish 3 g (98%) of compound 1.5.

Synthesis of compound 1.6. Into a 100-mL round-bottom flask, were placedcompound 1.5 (3 g, 8.92 mmol, 1.00 equiv), acetic acid (60 mL), Fe (1.5g, 26.79 mmol, 3.00 equiv). Reaction was stirred for 3 h at 50° C. in anoil bath. The resulting mixture was concentrated under vacuum. Theresidue was purified via flash column chromatography to provide 1.45 g(53%) of compound 1.6 as a yellow solid.

Synthesis of compound 1.7. Into a 50-mL round-bottom flask, were placedcompound 1.6 (1.4 g, 4.57 mmol, 1.00 equiv), CDI (2.9 g, 17.88 mmol,3.91 equiv), Et₃N (900 mg, 8.89 mmol, 1.95 equiv), and DMF (20 mL).Reaction was stirred for 4 h at 100° C. in an oil bath. The resultingmixture was concentrated under vacuum. The crude was purified via flashcolumn chromatography to provide 672 mg (44%) of compound 1.7 a whitesolid.

Synthesis of compound 1.8. Into a 100-mL round-bottom flask, were placedcompound 1.7 (672 mg, 2.02 mmol, 1.00 equiv), dichloromethane (30 mL)and NBS (360 mg, 2.02 mmol, 1.00 equiv). Reaction was stirred for 2 h atroom temperature. Upon completion solvents were removed in vacuo andcrude was purified via flash column chromatography to furnish 658 mg(79%) of compound 1.8 as a yellow solid.

Synthesis of compound 1.9. A 50-mL 3-necked round-bottom flask, wascharged with compound 1.8 (658 mg, 1.60 mmol, 1.00 equiv), THF (10 mL),diphenylmethanol (441 mg, 2.39 mmol, 1.50 equiv), DIAD (458 mg, 2.26mmol, 1.42 equiv) and PPh₃ (633 mg, 2.41 mmol, 1.51 equiv). Reaction wasstirred overnight at room temperature. Upon completion solvents wereremoved under reduced pressure and crude was purified using flash columnchromatography to furnish 745 mg (81%) of compound 1.9 as a white solid.

Synthesis of compound 1.10. A 50-mL round-bottom flask, was charged with2-(tributylstannyl)-1,3-oxazole (693 mg, 1.94 mmol, 1.47 equiv),compound 1.9 (745 mg, 1.31 mmol, 1.00 equiv), toluene (10 mL) andPd(PPh₃)₄ (220 mg, 0.19 mmol, 0.15 equiv). Reaction was stirredovernight at 110° C. in an oil bath. Upon completion of the reaction,the solvents were removed in vacuo and the crude material was purifiedusing flash column chromatography to furnish 420 mg (57%) of compound1.10 as a white solid.

Synthesis of compound 1.11. Into a 50-mL round-bottom flask, were placedcompound 1.10 (420 mg, 0.74 mmol, 1.00 equiv) and trifluoroacetic acid(10 mL), CF₃SO₃H (223 mg, 1.49 mmol, 2.00 equiv). The resulting solutionwas stirred for 2 h at room temperature. The reaction was then quenchedby the addition of 20 mL of aq. sodium bicarbonate and extracted with3×20 mL of ethyl acetate. Organic layers were combined and solvents wereremoved in vacuoo. Crude was purified using flash column chromatographyto furnish 120 mg (47%) of compound 1.11 as a white solid.

Synthesis of compound 1.12. Into a 50-mL round-bottom flask, were placedcompound 1.11 (120 mg, 0.35 mmol, 1.00 equiv), tetrahydrofuran (10 mL),TBDPSCl (138 mg, 0.50 mmol, 1.44 equiv) and imidazole (35 mg, 0.51 mmol,1.47 equiv). Reaction was stirred for 2 hours at room temperature. Uponcompletion solvent was removed under reduced pressure and the crude waspurified using flash column chromatography to provide 40 mg (20%) ofcompound 1.12 as a white solid.

Synthesis of compound 1.13. A 8-mL vial, was charged with compound 1.12(40 mg, 0.07 mmol, 1.00 equiv),(2R)-2-(5-fluoro-2-methoxyphenyl)-2-(oxan-4-yloxy)ethan-1-ol (28 mg,0.10 mmol, 1.51 equiv), THF (4 mL), PPh₃ (27 mg, 0.10 mmol, 1.50 equiv),and DIAD (20 mg, 0.10 mmol, 1.44 equiv). Reaction was stirred overnightat room temperature. Solvents were removed under reduced pressure andthe crude was purified using flash column chromatography to furnish 15mg (26%) of compound 1.13 as a white solid.

Synthesis of compound I-41. Into a 8-mL vial, were placed compound 1.12(15 mg, 0.02 mmol, 1.00 equiv), TBAF (15 mg, 0.06 mmol, 3.20 equiv), andTHF (2 mL). Reaction was stirred overnight at ambient temperature. Uponreaction completion, solvent was removed under reduced pressure andcrude product was purified using preparative HPLC to provide 3 mg (28%)of2-(4-((R)-2-(5-fluoro-2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-7-methyl-6-(oxazol-2-yl)-1,1-dioxido-3-oxo-3,4,4a,7a-tetra-hydro-2H-thieno[2,3-e][1,2,4]thiadiazin-2-yl)aceticacid, I-41 as a white solid.

LCMS (ES, m/z): 596 [M+H]⁺; ¹H NMR (300 MHz, CD₃OD): δ1.43-1.48 (m, 2H),δ1.66-1.68 (m, 2H), δ2.72 (s, 3H), δ3.32-3.41 (m, 2H), δ3.42-3.46 (m,1H), δ3.66-3.74 (m, 2H), δ3.85 (s, 3H), δ4.03-4.20 (m, 2H), δ4.43 (s,2H), δ5325-5.30 (m, 1H), δ6.92-7.03 (m, 2H), δ7.21-7.28 (m, 1H), δ7.98(s, 1H).

Example 2 Synthesis of Compound(R)-2-(4-(2-(5-fluoro-2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-7-methyl-6-(oxazol-2-yl)-1,1-dioxido-3-oxo-3,4-dihydro-2H-thieno[2,3-e][1,2,4]thiadiazin-2-yl)-2-methylpropanoicacid, I-42

Compound I-42 was prepared from compound 1.4 via multistep sequenceusing procedures described in Example 1. LCMS (ES, m/z): 624 [M+H]⁺; ¹HNMR(400 MHz, CD₃OD):δ1.53-1.64(m,2H), δ1.65-1.83(m,2H),δ1.84-1.97(m,6H), δ2.75(s,3H), δ3.39-3.50(m,2H), δ3.62-3.71(m,1H),δ3.84-3.97(m,5H), δ4.39-4.40(m,2H), δ5.37(m,1H), δ7.01-7.05(m,2H),δ7.20-7.30(m,2H), δ8.02(s,1H)

Example 3 Synthesis of2-(1-(2-methoxyphenethyl)-5-methyl-6-(oxazol-2-yl)-2,2-dioxido-4-oxo-1H-thieno[2,3-c][1,2,6]thiadiazin-3(4H)-yl)aceticacid, I-43

Synthesis of compound 3.2. A 100-mL round-bottom flask, was placed asolution of compound 3.1 (2 g, 10.80 mmol, 1.00 equiv) indichloromethane (50 mL). To the solution was added of sulfamoyl chloride(1.25 g, 10.82 mmol, 1.00 equiv) dropwise at 0° C. over 30 minutes.Solution was initially stirred for 30 minutes at 0° C. and Et₃N (1.1 g,10.87 mmol, 1.00 equiv) was added dropwise over 30 minutes with stirringat 0° C. Reaction was then stirred for 16 h at room temperature and uponcompletion quenched by the addition of 30 mL of aq. NH₄Cl (30 mL).Resulting solution was extracted with 3×50 mL of dichloromethane.Organic layers were combined, washed with 3×20 mL of water and driedover anhydrous sodium sulfate. Solvent was removed under reducedpressure and crude was purified using flash column chromatography toprovide 600 mg (21%) of compound 3.2 as a yellow solid.

Synthesis of compound 3.3. Into a 25-mL round-bottom flask, was placed asolution of compound 3.2 (50 mg, 0.19 mmol, 1.00 equiv) in benzene (5mL), and aq. sodium hydroxide (1 mL, 20%). Reaction was stirred for 16 hat room temperature. Upon completion of the reaction 10 mL of water wereadded and the resulting solution was extracted with 2×10 mL of ethylacetate. Aqueous layers were combined and pH value was adjusted to 7using aq. HCl (2 mol/L). Solvents were removed under reduced pressure,crude dissolved in 1 mL of methanol and purified using preparative TLCto provide 20 mg (48%) of compound 3.3 as a dark green solid.

Synthesis of compound 3.4. Into a 50-mL round-bottom flask, was placed asolution of compound 3.3 (1.2 g, 5.50 mmol, 1.00 equiv) inN,N-dimethylformamide (10 mL). Sodium hydride was added (110 mg, 0.50equiv) at 0° C. The mixture with stirring for 30 min at 0° C. followedby benzyl 2-bromoacetate (1.05 g, 4.58 mmol, 1.00 equiv). Reaction wasstirred for 30 min at 0° C. and then quenched by the addition of 20 mLof aq. NH₄Cl (20 mL). The resulting solution was extracted with 3×20 mLof ethyl acetate and the organic layers combined and dried overanhydrous sodium sulfate. Solvents were removed under vacuum and crudepurified using flash column chromatography and preparative HPLC tofurnish 100 mg (5%) of compound 3.4 as an off-white solid.

Synthesis of compound 3.5. A 8 mL vial under nitrogen, was charged witha solution of compound 3.4 (60 mg, 0.16 mmol, 1.00 equiv) in THF (1 mL),2-(2-methoxyphenyl)ethan-1-ol (25 mg, 0.16 mmol, 1.20 equiv), PPh₃ (43mg, 0.16 mmol, 1.50 equiv) and DIAD (33 mg, 0.16 mmol, 1.50 equiv). Theresulting solution was stirred for 16 h at room temperature. Uponcompletion of the reaction, mixture was directly loaded onto a flashcolumn to furnish 70 mg (85%) of compound 3.5 as an off-white solid.

Synthesis of compound 3.6. Into a 8-mL vial, was placed a solution ofcompound 3.5 in dichloromethane (3 mL) and NBS (23 mg, 0.13 mmol, 1.00equiv). Reaction was stirred for 2 hours at room temperature andquenched by the addition of 2 mL of water/ice. The resulting solutionwas extracted with 3×10 mL of ethyl acetate and the organic layerscombined and dried over anhydrous sodium sulfate. Upon filtrationsolvents were removed under a reduced pressure and resulting crude waspurified by preparative TLC to furnish 70 mg (93%) of compound 3.7 as anoff-white solid.

Synthesis of compound I-43. A 8-mL vial kept under nitrogen, was chargedwith a solution of compound 3.7 (70 mg, 0.12 mmol, 1.00 equiv) intoluene (1 mL), 2-(tributylstannyl)-1,3-oxazole (78 mg, 0.22 mmol, 1.80equiv) and Pd(PPh₃)₄ (28 mg, 0.02 mmol, 0.20 equiv). Reaction wasstirred for 16 h at 110° C. in an oil bath. Upon completion was thereaction, solids were filtered and resulting residue was purified bypreparative TLC and preparative HPLC to furnish 40 mg (58%) of compound3.7 as an off-white solid and 7.5 mg (13%) of2-(1-(2-methoxyphenethyl)-5-methyl-6-(oxazol-2-yl)-2,2-dioxido-4-oxo-1H-thieno[2,3-c][1,2,6]thiadiazin-3(4H)-yl)aceticacid, I-43 as a white solid.

LCMS (ES, m/z): 478 [M+H]⁺; ¹H NMR (300 MHz, DMSO-d₆): δ 8.20(s,1H),7.35(s,1H), 7.19˜7.14(m,1H), 7.07(d,J=7.2 Hz,1H), 6.90(d,J=8.4 Hz, 1H),6.81˜6.76(m,1H), 4.32(s,2H), 4.08˜4.04(m,2H), 3.71(s,3H),2.95˜2.90(m,2H), 2.65(s,3H).

Example 4 Synthesis of2-(1-(2-methoxyphenethyl)-5-methyl-6-(oxazol-2-yl)-2,2-dioxido-4-oxo-1H-thieno[2,3-c][1,2,6]thiadiazin-3(4H)-yl)acetamide,I-44

An 8-mL round-bottom flask under nitrogen was charged with a solution ofcompound I-43 (25 mg, 0.05 mmol, 1.00 equiv) in dichloromethane (2 mL),NH₄Cl (3 mg, 0.06 mmol, 2.00 equiv), 4-dimethylaminopyridine (7 mg, 0.06mmol, 2.00 equiv) and DCC (11 mg, 0.05 mmol, 2.00 equiv). Reaction wasstirred for 16 h at 50° C. in an oil bath and then quenched by theaddition of 3 mL of water/ice. The resulting solution was extracted with3×5 mL of dichloromethane, organic layers combined and dried overanhydrous sodium sulfate. Solvents were removed under reduced pressureand crude was purified by preparative TLC and preparative HPLC tofurnish 3.6 mg (14%) of compound I-44 as a white solid. LCMS (ES, m/z):477 [M+H]⁺; ¹H NMR (300 MHz, DMSO-d₆): δ8.25(s,1H), 7.62(s,1H), 7.40(s,1H), 7.26˜7.21(m,2H), 7.15(d, J=7.2 Hz,1H), 7.02˜6.96(m,1H),6.85(m,1H), 4.33(s,2H), 4.11˜4.06(m,2H), 3.78(s,3H), 3.02-2.92(m,2H),2.70(s,3H).

Example 5 Synthesis of(R)-2-(4-(2-(5-fluoro-2-methoxyphenyl)-2-isopropoxyethyl)-7-methyl-6-(oxazol-2-yl)-1,1-dioxido-3-oxo-3,4-dihydro-2H-thieno[2,3-e][1,2,4]thiadiazin-2-yl)-2-methylpropanoicacid, I-45

Synthesis of compound 5.2. A 100-mL 3-necked round-bottom flask keptunder nitrogen, was charged with compound 2.8 (1.5 g, 2.46 mmol, 1.00equiv), DIAD (0.74 mg, 3.66 mmol, 1.5 equiv), THF (20 mL),(2R)-2-(5-fluoro-2-methoxyphenyl)-2-(propan-2-yloxy)ethan-1-ol, compound5.1 (830 mg, 3.64 mmol, 1.48 equiv) and PPh₃ (960 mg, 3.66 mmol, 1.49equiv). Reaction was stirred overnight at room temperature. Uponcompletion of the reaction, solvents were removed under vacuum and crudepurified using flash column chromatography to provide 1.3 g of compound5.2 as a white solid.

Synthesis of compound I-45. Compound I-45 was prepared from compound 5.1using protocol described in Example 1; LCMS (ES, m/z): 582 [M+H]⁺; ¹HNMR(300 MHz, DMSO): δ1.13-1.15(dd, 3H), δ1.23-1.26 (dd, 3H),δ1.80-1.85(d, 6H), δ2.72(s, 3H), δ3.53-3.61(m, 1H), δ3.83(s,3H),δ4.28-4.30(m,2H), δ5.11-5.14(t, 1H), δ7.02-7.07(m, 1H), δ7.11-7.25(m,2H), δ7.40(s, 1H), δ8.23(s, 1H), δ13.25(s, 1H).

Example 6 Synthesis of Compound(R)-2-(4-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-7-methyl-6-(oxazol-2-yl)-1,1-dioxido-3-oxo-3,4-dihydro-2H-thieno[2,3-e][1,2,4]thiadiazin-2-yl)-2-methylpropanoicacid, I-46

Compound I-46 was prepared from compounds 2.8 and 6.1 using a proceduredescribed in Example 1; LCMS (ES, m/z): 606 [M+H]⁺; ¹H NMR (400 MHz,CD₃OD): δ1.41-1.42(d, 1H), δ1.53-1.55 (m, 1H), δ1.65-1.15(m, 2H),δ1.91(s, 3H), δ2.73(s, 3H), δ3.33-3.44(m, 2H), δ3.58-3.63(m,1H),δ3.82-3.88(m,1H), δ3.90(s, 3H), δ3.92-3.98(m, 1H), δ4.38-4.43(m, 2H),δ5.41-5.44(m, 1H), δ7.00-7.03(t, 2H), δ7.31-7.35(m, 2H), δ7.48-7.50(d,1H), δ7.98(s, 1H).

Example 7 Synthesis of2-(4-((R)-2-(((1s,4S)-4-hydroxycyclohexyl)oxy)-2-(2-methoxyphenyl)ethyl)-7-methyl-6-(oxazol-2-yl)-1,1-dioxido-3-oxo-3,4-dihydro-2H-thieno[2,3-e][1,2,4]thiadiazin-2-yl)-2-methylpropanoicacid, I-47

Synthesis of compound 7.2. Compound 7.2 was prepared from compounds 2.8and 7.1 using procedure described in Example 1.

Synthesis of compound 7.3. Compound 7.3 was prepared from compound 7.2using procedure described in Example 1.

Synthesis of compound I-47. Into a 50-mL 3-necked round-bottom flask,was placed compound 7.3 (55 mg, 0.09 mmol, 1.00 equiv) as a solution inTHF (10 mL). Solution was cooled to −78° C. and L-selectride (0.26 mL,3.00 equiv, 1M) was added drop wise. The resulting solution was stirredfor 1 hour at −78° C. Reaction was then quenched by the addition of 10mL of NH₄Cl (aq.). The resulting solution was extracted with 2×10 mL ofethyl acetate and the organic layers were combined and solvent wasremoved under reduced pressure. The crude was purified using preparativeHPLC to provide 20 mg (36%) of compound I-47 as a white solid. LCMS (ES,m/z): 620 [M+H]⁺; 642 [M+Na]⁺; ¹H NMR(300 MHz, CD₃OD): δ1.26-1.70(m,8H), 1.84-1.90(d, 6H), δ2.67(s, 3H), δ3.43(m, 1H), δ3.50(m,1H), δ3.84(s,3H), δ4.27-4.42(m, 2H), δ5.28-5.30(m, 1H), δ6.94-6.97(m, 2H),δ7.24-7.29(m, 2H), δ7.44-7.52(m, 1H), δ7.93(s, 1H).

Example 8 Synthesis of (R)-ethyl2-(1-(benzyloxy)-2-methyl-1-oxopropan-2-yl)-4-(2-(5-fluoro-2-methoxyphenyl)-2-isopropoxyethyl)-7-methyl-3-oxo-3,4-dihydro-2H-thieno[2,3-e][1,2,4]thiadiazine-6-carboxylate1,1-dioxide, I-48

Synthesis of compound 8.1. A 100-mL pressure tank reactor (10 atm)purged and maintained under a blanket of CO, was charged with compound2.5 (2 g, 3.30 mmol, 1.00 equiv), ethanol (40 mL), Pd(dppf)Cl₂ (120 mg,0.16 mmol, 0.05 equiv), and triethylamine (670 mg, 6.62 mmol, 2.00equiv). Reaction was stirred overnight at 120° C. in an oil bath. Uponcompletion of the reaction, solvent was removed under reduced pressureand the crude was purified using flash column chromatography to yield in1.6 g (81%) of compound 8.1 as a white solid.

Synthesis of compound 8.2. Into a 50-mL round-bottom flask, were placedcompound 8.1 (1.6 g, 2.67 mmol, 1.00 equiv), CF₃SO₃H (800 mg, 5.34 mmol,2.00 equiv), trifluoroacetic acid (10 mL). Reaction was stirred for 3hours at room temperature and then quenched by the addition of 20 mL ofsodium bicarbonate. The resulting solution was extracted with 2×20 mL ofethyl acetate, organic layers were combined and concentrated undervacuum. The crude was purified using flash column chromatography toprovide 1 g (99%) of compound 8.2 as a yellow solid.

Synthesis of compound 8.3. A 100-mL, 3-necked round-bottom flask, wascharged with compound 8.2 (1 g, 2.66 mmol, 1.00 equiv) in ethyl acetate(50 mL), Et₃N (530 mg, 5.24 mmol, 1.97 equiv), BnOH (0.34 g) and T3P (2g). Reaction was stirred overnight at room temperature. Upon completionsolvent was removed under reduced pressure and the crude was purifiedusing flash column chromatography to provide 0.8 g (65%) of compound 8.3as a white solid.

Synthesis of Compound I-48. Compound I-48 was prepared from compound 8.3using procedure described in Example 1. LCMS (ES, m/z): 677 [M+H]⁺; 699[M+Na]⁺; ¹H NMR (300 MHz, CDCl₃): δ 0.90 (d, 3H), 1.01 (d, 3H), δ1.41(t, 3H), δ1.93-2.01 (dd, 6H), δ2.71 (s, 3H), δ3.38-3.47 (m, 1H), δ3.80(s, 3H), δ3.85-3.93 (m, 2H), δ4.30-4.41 (m, 2H), δ5.09-5.13 (m, 1H),δ5.16 (s, 2H), δ6.72-6.77 (m, 1H), δ6.90-6.97 (m, 1H), δ7.24-7.31 (m,6H).

Example 9 Synthesis of Compound2-(7-(2-methoxyphenethyl)-3-methyl-2-(oxazol-2-yl)-4-oxothieno[2,3-d]pyridazin-5(4H)-yl)aceticacid, I-49

Synthesis of Compound 9.2. A 500-mL 3-necked round-bottom flask wascharged with solution of compound 9.1 (20 g, 146.90 mmol, 1.00 equiv) inpyridine (250 mL), propanedioic acid (18.3 g, 175.86 mmol, 1.20 equiv),and piperidine (2.5 g, 29.36 mmol, 0.20 equiv). Reaction was stirredovernight at 85° C. Upon completion, solvents were reduced under vacuumand pH value of the solution was adjusted to 3.0 using HCl. Resultingsolids were collected by filtration, which provided 25.6 g (98%) ofcompound 9.2 as a white solid.

Synthesis of Compound 9.3. Into a 2-L 3-necked round-bottom flask, wasplaced a solution of compound 9.2 (25.6 g, 143.67 mmol, 1.00 equiv) inmethanol (1 L) and Pd/C (8 g). Hydrogen gas was introduced and reactionwas stirred overnight at room temperature. Solids were filtered out, andsolvents removed under reduced pressure to furnish 25.7 g (99%) ofcompound 9.3 as a white solid.

Synthesis of Compound 9.4. Into a 100-mL round-bottom flask, were placedcompound 9.3 (1.0 g, 5.55 mmol, 1.00 equiv), CH₂Cl₂ (25 mL),chloro(ethoxy)-methanone (600 mg, 5.53 mmol, 1.00 equiv) and Et₃N (1.68g, 16.60 mmol, 3.00 equiv). Reaction was stirred for 1 h at 0° C.followed by addition of methyl(methoxy)amine hydrochloride (540 mg, 5.54mmol, 1.00 equiv). The solution was stirred for an additional 1 h atroom temperature and the reaction was then quenched by the addition of10 mL of water. The resulting solution was extracted with 3×20 ml, ofethyl acetate, organic layers combined and washed with 3×10 mL of water.Solvents were removed in vacuoo to provide 1.0 g (81%) of compound 9.4as a white solid.

Synthesis of Compound 9.6. A 500-mL 3-necked round-bottom flask wascharged with tert-butyl nitrite (21.6 g, 209.47 mmol, 1.30 equiv),dibromocopper (39.2 g, 175.51 mmol, 1.10 equiv) and acetonitrile (210mL). Solution of compound 9.5 (30 g, 161.95 mmol, 1.00 equiv) in MeCN(90 mL) was added drop wise over a 5 hour period. Reaction was stirredfor 1 hour at room temperature and then directly purified via flashcolumn chromatography to provide 11 g (21%) of compound 9.6 as anoff-white solid.

Synthesis of Compound 9.7. Into a 500-mL round-bottom flask, were placedcompound 9.6 (18 g, 54.87 mmol, 1.00 equiv), methanol (200 mL) and Pd/C(1 g). Hydrogen gas was introduced and the reaction was stirred for 20 hat room temperature. Solids were filtered and solvent removed underreduced pressure to yield 9 g (96%) of compound 9.7 as a off-whitesolid.

Synthesis of Compound 9.8. A 250-mL round-bottom flask, was charged withcompound 9.7 (11.0 g, 64.6 mmol, 1.00 equiv), methanol (60 mL), water(30 mL), sodium hydroxide (6.0 g, 150.01 mmol, 2.32 equiv). Theresulting solution was stirred for 2 h at room temperature. Mixture wasthen concentrated under reduced pressure and the pH value of thesolution was adjusted to 3 with HCl. Resulting solids were collected byfiltration to provide 8.0 g (87%) of compound 9.8 as a white solid.

Synthesis of Compound 9.9. A 250-mL 3-necked round-bottom under nitrogenwas charged with bis(propan-2-yl)amine (7.0 g, 69.18 mmol, 2.02 equiv)and tetrahydrofuran (100 mL). To the solution was added n-BuLi (33.2 mL)drop wise while stirring at −30° C. The solution was then warmed up andstirred for 0.5 hours at −10° C. Compound 9.8 (4.88 g, 34.32 mmol, 1.00equiv) in THF (25 mL) was added then slowly while stirring at −78° C.,followed by addition of HMPA solution (1.23 g, 6.86 mmol, 0.20 equiv) inTHF (5 mL). Reaction was stirred for 1 hour at −78° C. To this mixturewas added a solution of compound 9.4 (9.2 g, 41.21 mmol, 1.20 equiv) inTHF (25 mL) drop wise with stirring at −78° C. Reaction was stirred for45 min at room temperature and then quenched by the addition of 150 mLof water. The resulting solution was extracted with 3×100 mL of ethylacetate, organic layers were combined and solvents were removed underreduced pressure. The crude was purified using flash columnchromatography to provide 10 g (96%) of compound 9.9 as yellow oil.

Synthesis of Compound 9.10. Into a 100-mL round-bottom flask, wereplaced compound 9.9 (5.6 g, 18.40 mmol, 1.00 equiv), iodoethane (3.5 g,22.44 mmol, 1.20 equiv), N,N-dimethylformamide (30 mL) and K₂CO₃ (5.1 g,36.63 mmol, 2.00 equiv). Reaction was stirred for 3 h at 50° C. and thenquenched by the addition of 10 mL of water. Resulting solution wasextracted with 3×20 mL of ethyl acetate, organic layers were combinedand solvents were removed under vacuum to provide 5.2 g (85%) ofcompound 9.10 as an off-white solid.

Synthesis of Compound 9.11. A 500-mL round-bottom flask, was chargedcompound 9.10 (2.5 g, 7.52 mmol, 1.00 equiv), ethanol (250 mL), andhydrazine (5.76 g, 179.75 mmol, 23.9 equiv.). Reaction was stirred for30 h at room temperature. Upon completion of the reaction, solvents wereremove under reduced pressure and crude purified by re-crystallizationto furnish 2.2 g (97%) of compound 9.11 as an off-white solid.

Synthesis of Compound 9.12. Into a 25-mL round-bottom flask, were placedcompound 9.11 (1.0 g, 3.33 mmol, 1.00 equiv), CH₂Cl₂ (10 mL) and NBS(593 mg, 3.33 mmol, 1.00 equiv.). The resulting solution was stirred for10 hours at room temperature and then concentrated under vacuum. Thecrude product was purified by re-crystallization to provide 1.0 g (79%)of compound 9.12 as a white solid.

Synthesis of Compound 9.13. A 25-mL round-bottom flask, was charged withcompound 9.12 (1 g, 2.64 mmol, 1.00 equiv), N,N-dimethylformamide (10mL), benzyl 2-bromoacetate (1.2 g, 5.24 mmol, 2.00 equiv) and K₂CO₃ (548mg, 3.94 mmol, 1.50 equiv). Reaction was stirred for 2 h at roomtemperature and then quenched by addition of 5 mL of water. Theresulting solution was extracted with 3×10 mL of ethylacetate, organiclayers were combined and concentrated under vacuum. The crude waspurified by crystallization to provide 1.3 g (93%) of compound 9.13 as alight yellow solid.

Synthesis of Compound 9.14. Into a 25-mL round-bottom flask purged andmaintained with an inert atmosphere of nitrogen, were placed compound9.13 (1.5 g, 2.84 mmol, 1.00 equiv), 2-(tributylstannyl)-1,3-oxazole(1.53 g, 4.27 mmol, 1.50 equiv), toluene (10 mL) andtetrakis(triphenylphosphane) palladium (0.658 g, 569.42 mmol, 0.20equiv). Reaction was stirred for 10 h at 110° C. and then concentratedunder vacuum. The crude was purified using flash column chromatographyto furnish 270 mg (18%) of benzyl compound 9.13 as a light yellow solid.

Synthesis of Compound I-49. Into a 50-mL round-bottom flask, were placedcompound 9 (100 mg, 0.19 mmol, 1.00 equiv), methanol (20 mL) andPd(OH)₂/C (20 mg). Reaction was stirred overnight at room temperatureunder atmosphere of hydrogen gas. The solids were filtered out andsolvents removed under vacuum to yield 36 mg (44%) of2-(7-(2-methoxyphenethyl)-3-methyl-2-(oxazol-2-yl)-4-oxothieno[2,3-d]pyridazin-5(4H)-yl)acetic acid, 1-49 as a white solid. LCMS (ES, m/z): 426 [M+H]⁺;¹H NMR (300 MHz, CD₃OD): δ2.62 (s, 3H), δ3.10-3.21 (m, 4H), δ3.87 (s,3H), δ4.86 (s, 2H), δ7.04-7.07 (m, 1H), δ7.25 (s, 1H), δ7.46 (s, 1H),δ7.83-7.93 (m, 3H).

Example 10

In Vitro Acetyl-CoA Carboxylase (ACC) Inhibition Assay

An exemplary procedure for the in vitro ACC inhibition assay, which canbe used to determine the inhibitory action of compounds of the inventiontoward either ACCT or ACC2, follows. The ADP-Glo™ Kinase Assay kit fromPromega is used. The ADP-Glo™ Kinase Assay is a luminescent ADPdetection assay to measure enzymatic activity by quantifying the amountof ADP produced during an enzyme reaction. The assay is performed in twosteps; first, after the enzyme reaction, an equal volume of ADP-Glo™Reagent is added to terminate the reaction and deplete the remainingATP. Second, the Kinase Detection Reagent is added to simultaneouslyconvert ADP to ATP and allow the newly synthesized ATP to be measuredusing a luciferase/luciferin reaction. Luminescence can be correlated toADP concentrations by using an ATP-to-ADP conversion curve. The detailedprocedure is as follows. 50 μL of the compound being tested (600 uM inDMSO) is added to a 384-well dilution plate. The compound is diluted 1:3in succession in DMSO for each row for 11 wells. 0.5 μL ACC2 workingsolution is added to 384-well white Optiplate assay plate. 0.5 μLdiluted compound solution in each column from step 2 is added to theassay plate, each row containing 2 replicates. For the last 2 rows, add0.5 μL negative control (DMSO) in one row and 0.5 μL positive control(compound I-97) in the other. The plates are incubated at roomtemperature for 15 minutes. 5 μL substrate working solution is added toeach well to initiate reaction. Final ACC2 reaction concentrationsconsist of: 5 nM ACC2, 20 μM ATP, 20 μM acetyl-CoA, 12 mM NaHCO3, 0.01%Brij35, 2 mM DTT, 5% DMSO, test compound concentrations: 30 μM, 10 μM,3.33 μM, 1.11 μM, 0.37 μM, 0.123 μM, 0.0411 μM, 0.0137 μM, 0.00457 μM,0.00152 μM, and 0.00051 μM. Plates are incubated at room temperature for60 minutes. 10 μL ADP glo reagent is added. Plates are incubated at roomtemperature for 40 minutes. 20 μL kinase detection reagent is added.Plates are incubated at room temperature for 40 minutes, then read on aPerkin Elmer EnVision 2104 plate reader for luminescence as RelativeLight Units (RLU).

Data for each concentration, as well as the positive and negativecontrols are averaged, and the standard deviation calculated. Percentinhibition is calculated by the formula: 100×(average negativecontrol−compound)/(average negative control−average positive control).The IC50 for each compound is calculated by fitting the data with anon-linear regression equation: Y=Bottom+(Top-Bottom)/(1+10^((LogIC50−X)*HillSlope)), where X is the log of compound concentration and Yis percent inhibition.

In some embodiments, compounds have an IC₅₀ of 5-20 μM. In someembodiments, compounds have an IC₅₀≦5 μM. In some embodiments, compoundshave an IC₅₀≦1 μM. In some embodiments, compounds have an IC₅₀≦0.1 μM.In some embodiments, compounds have an IC₅₀≦0.01 μM. In someembodiments, compounds have an IC₅₀≦0.001 μM.

The results of the in vitro ACC2 inhibition assay are set forth in Table2. The compound numbers correspond to the compound numbers in Table 1.Compounds having an activity designated as “AAA” provided an IC₅₀≦0.1μM; compounds having an activity designated as “AA” provided an IC₅₀≦1μM; compounds having an activity designated as “A” provided an IC₅₀≦5μM; compounds having an activity designated as “B” provided an IC₅₀ of5-20 μM; compounds having an activity designated as “C” provided an IC₅₀of 20-50 μM; and compounds having an activity designated as “D” providedan IC₅₀≧50 μM

TABLE 2 Results of in vitro ACC2 inhibition assay Cpd # ACC2 IC₅₀ I-41AAA I-42 A I-43 B I-44 B I-45 B I-46 B I-47 B I-48 B I-49 D

Example 11

Thermal Shift Assay

Compounds of the present invention are evaluated in a thermal shiftassay using methods substantially similar to those described by Vedadiet al. “Chemical screening methods to identify ligands that promoteprotein stability, protein crystallization, and structuredetermination.” PNAS (2006) vol. 103, 43, 15835-15840, the entirety ofwhich is incorporated herein by reference.

The thermal shift assay tests the ability of compounds of the inventionto bind effectively to and elicit a conformational change on the proteinresulting in its allosteric inhibition mechanism.

Example 12

[¹⁴C] Acetate Incorporation Assay

Compounds of the present invention are evaluated in a [¹⁴C] AcetateIncorporation Assay. An exemplary procedure for the assay, whichmeasures the incorporation of isotopically labeled acetate into fattyacids, follows. HepG2 cells are maintained in T-75 flasks containingDMEM supplemented with 2 mM 1-glutamine, penicillin G (100 units/ml),streptomycin 100 μg/ml with 10% FBS and incubated in a humidifiedincubator with 5% CO2 at 37° C. Cells are fed every 2-3 days. On Day 1.cells are seeded in 24 well plates at a density of 1.2×105 cells/ml/wellwith the growth medium. On Day 3 the medium is replaced with freshmedium containing 10% FBS. On Day 4 the medium is replaced with 0.5 mlof fresh medium containing test compound (in DMSO; final [DMSO] is 0.5%)and the cells are incubated at 37° C. for 1 hour. To one copy of plate,4 ul of [2-¹⁴C] acetate (56 mCi/mmol; 1 mCi/ml; PerkinElmer) is addedand the cells are incubated at 37° C., 5% CO2 for 5 hrs. To a secondcopy of plate, 4 ul of cold acetate are added and the cells areincubated at 37° C., 5% CO2 for 5 hrs. This plate is used for proteinconcentration measurement. Medium is removed and placed in a 15 mlcentrifuge tube (BD, Falcon/352096). Cells are rinsed with 1 ml PBS,then aspirated, and the rinse and aspiration steps are repeated. 0.5 mlof 0.1N NaOH are added to each well and let sit at RT to dissolve cellmonolayer. The remaining cell suspension is pooled with medium. For theprotein determination plate, an aliquot is removed for proteindetermination (25 ul). 1.0 ml of EtOH and 0.17 ml 50% KOH are added totubes containing medium and cell suspensions. Cells are incubated at 90°C. for 1 hr, then cooled to room temperature. 5 ml petroleum ether isadded per tube, shaken vigorously, centrifuged at 1000 rpm for 5 min,and 500 uL of the petroleum ether layer is transferred to tubes forMicrobeta reading, then 2 ml Aquasol-2 ae added to each tube, the tubesare shaken and counted with a Microbeta Liquid Scintillation Counter(Perkin Elmer).

The remaining petroleum ether layer is discarded and the aqueous phasereserved for fatty acid extractions. The aqueous phase is acidified with1 ml of concentrated HCl, checking pH of one or two extracts to makesure pH is below 1. 5 ml of petroleum ether is added per tube, shakenvigorously, centrifuged at 1000 rpm for 5 min, and 4 ml of the petroleumether layer is transferred to a new glass tube (10*18 mm). 5 ml ofpetroleum ether is added per tube, shaken vigorously, centrifuged at1000 rpm for 5 min, and 5 ml of the petroleum ether layer is transferredto the glass tube, and the extraction repeated again. The petroleumether extracts are pooled and evaporated to dryness overnight. On Day 5the residue from the petroleum ether fractions is resuspended in 120 uLof chloroform-hexane (1:1) containing 200 ug of linoleic acid as acarrier. 5 uL of this is spotted onto silica gel sheets, and the platesdeveloped using heptane-diethyl ether-acetic acid (90:30:1) as eluent.The fatty acid band is visualized with iodine vapor and thecorresponding bands are cut out into scintillation vials. 2 ml ofAquasol-2 is added to each vial, and the vials are shaken and counted ona scintillation counter.

The [¹⁴C] Acetate Incorporation Assay illustrates the ability ofcompounds of the invention to inhibit incorporation of isotopicallylabeled acetate into fatty acids. In some embodiments, the inhibitionoccurs with an IC₅₀ of less than 100 nM.

Example 13

Anti-Fungal Activity Assay

Compounds of the present invention are evaluated in an Anti-FungalActivity Assay. An exemplary procedure for the assay, which measures thesusceptibility of various Candida species to anti-fungal compounds,follows. Compounds to be tested (including fluconazole and amphotericinB) are dissolved in DMSO to obtain a solution having a concentration of1 mg/mL. These stock solutions are sterile filtered using a 0.22 umnylon syringe filter, then diluted in sterile water to achieve a finalconcentration of 128 ug/mL.

All species are grown from frozen stock by directly plating on tofreshly prepared Sabouraud Dextrose agar (BD, Difco) and incubatedovernight in ambient air at 35° C. for 24 h. A direct suspension isprepared in RPMI 1640+MOPS (Lonza, Biowhittaker) by taking individualcolonies from the overnight cultures using sterile swabs soaked insterile saline. The concentration of the suspension is determined usingpre-determined standard curves. These suspensions are then diluted downto 5×10³ CFU/mL to achieve a final concentration of 2.5×10³ CFU/mL onceadded to the microtiter plate as per CLSI guidelines (M27-A3, Vol. 28No. 14).

Broth microtiter MIC challenge plates are prepared following CLSIguidelines (M27-A3, Vol. 28 No. 14). The original CLSI guidelinesfocused on reading Candida MICs after 48 h of incubation. As readingafter only 24 h offers a clear advantage of patient care, QC limits arebeing established for all drugs at 24 h. That being said there are noknown interpretive breakpoints for amphotericin B at 24 h and thecurrent fluconazole interpretive breakpoints are based on a 48 hreading. The MIC breakpoints for the test compounds are recorded at 48h, and for the soraphen control the 24 h time-point is added. All MICdeterminations are achieved by visually comparing the growth found inthe antibiotic challenged wells to that of the growth control. The firstwell found in the dilution scheme that shows no growth (or completeinhibition) is recorded as the MIC.

In some embodiments, the Anti-Fungal Activity Assay illustrates thatcompounds of the invention have anti-fungal activity MICs in the lowug/mL range.

Example 14

Cancer Cell Viability Assay

Compounds of the invention are also assayed in a Cancer Cell ViabilityAssay as described by Beckers et al. “Chemical Inhibition of Acetyl-CoACarboxylase Induces Growth Arrest and Cytotoxicity Selectively in CancerCells” Cancer Res. (2007) 67, 8180-8187. An exemplary procedure for theassay, which measures the percentage of cancer cells surviving followingadministration of inhibitor compounds, follows.

LNCaP (prostate cancer cell line) cells plated at 4×10⁵ per 6 cm dishare incubated at 37° C., and the following day they are treated withincreasing concentrations of inhibitor compounds and incubated. Viablecells and the percentage of dead cells are counted and calculated everyday for 5 days from day 0, using trypan blue staining

In some embodiments, the Cancer Cell Viability Assay shows the abilityof compounds of the invention to completely inhibit cell populationgrowth at a concentration of 5 uM.

Example 15

In Vivo Fatty Acid Synthesis Study

Compounds of the present invention are also assayed in an In Vivo FattyAcid Synthesis Study as described by Harwood et al.“Isozyme-nonselective N-Substituted Bipiperidylcarboxamide Acetyl-CoACarboxylase Inhibitors Reduce Tissue Malonyl-CoA Concentrations, InhibitFatty Acid Synthesis, and Increase Fatty Acid Oxidation in CulturedCells and in Experimental Animals” Journal of Biological Chemistry(2008) 278, 37099-37111. An exemplary procedure for the assay, whichmeasures the amount of radioactive [C¹⁴]-acetate incorporated into ratliver tissue, follows.

Animals given food ad water ad libitum are treated orally at a volume of1.0 mL/200 g body weight (rat) with either an aqueous solutioncontaining 0.5% methylcellulose (vehicle), or an aqueous solutioncontaining 0.5% methylcellulose plus test compound. One to four hoursafter compound administration, animals receive an intraperitonealinjection of 0.5 mL of [C¹⁴]-acetate (64 uCi/mL; 56 uCi/mL). One hourafter radiolabeled acetate administration, animals are sacrificed by CO₂asphyxiation and two 0.75 g liver pieces are removed and saponified at70 degrees C. for 120 minutes in 1.5 mL of 2.5M NaOH. Aftersaponification, 2.5 mL of absolute ethanol are added to each sample andthe solutions are mixed and allowed to stand overnight. Petroleum ether(4.8 mL) is then added to each sample, and the mixtures are first shakenvigorously for 2 minutes and then centrifuged at 1000×g in a benchtopSorvall for 5 minutes. The resultant petroleum ether layers, whichcontain non-saponifiable lipids, are removed and discarded. Theremaining aqueous layer is acidified to pH <2 by the addition of 12M HCland extracted two times with 4.8 mL of petroleum ether. The pooledorganic fractions are transferred to liquid scintillation vials, driedunder nitrogen, dissolved in 7 mL of Aquasol liquid scintillation fluid,and assessed for radioactivity using a Beckman 6500 liquid scintillationcounter. Results are recorded as disintigrations per minute (DPM) permilligram of tissue.

In some embodiments, the In Vivo Fatty Acid Synthesis Study shows thatthe ED₅₀ of compounds of the invention is less than 0.3 mg/Kg bodyweight.

Example 16

Respiratory Quotient Measurement Assay

Compounds of the present invention are also assayed in a RespiratoryQuotient Measurement Assay, as described by Harwood et al.“Isozyme-nonselective N-Substituted Bipiperidylcarboxamide Acetyl-CoACarboxylase Inhibitors Reduce Tissue Malonyl-CoA Concentrations, InhibitFatty Acid Synthesis, and Increase Fatty Acid Oxidation in CulturedCells and in Experimental Animals” Journal of Biological Chemistry(2008) 278, 37099-37111. An exemplary procedure for the assay, whichmeasures the ratio of carbon dioxide production to oxygen consumption inrats, follows.

Male Sprague-Dawley rats (350-400 g) housed under standard laboratoryconditions, either fed chow, fasted, or fasted and refed a diet high insucrose for 2 days prior to experimentation are removed from their homecages, weighed, and placed into sealed chambers (43 “43” 10 cm) of thecalorimeter (one rat per chamber). The chambers are placed in activitymonitors. The calorimeter is calibrated before each use, air flow rateis adjusted to 1.6 liters/min, and the system settling and samplingtimes are set to 60 and 15 s, respectively. Base-line oxygenconsumption, CO₂ production, and ambulatory activity are measured every10 min for up to 3 h before treatment. After collecting base-line data,the chambers are opened and rats are given a 1.0-ml oral bolus of eitheran aqueous 0.5% methylcellulose solution (vehicle control) or an aqueous0.5% methylcellulose solution containing test compound and then returnedto the Oxymax chambers. Measurements are made every 30 min for anadditional 3-6 h after dose. Fed vehicle controls are used to assesseffects produced by vehicle administration and by drift in the RQmeasurement during the course of the experimentation (if any).Overnight-fasted, vehicle-treated controls are used to determine maximalpotential RQ reduction. Results are plotted as their absolute RQ value(±SEM) over time.

In some embodiments, the In Vivo Fatty Acid Synthesis Study shows thatcompounds of the invention decrease RQ to approximately 80-90% of itsbaseline value, and show dose-dependent decreases in RQ.

Example 17

Propidium Iodide Cell Death Assay

Compounds of the present invention are also assayed in a propidiumiodide (PI) cell death assay, based on the procedure described by vanEngeland et al. “A novel assay to measure loss of plasma membraneasymmetry during apoptosis of adherent cells in culture” Cytometry(1996) 24 (2), 131-139. An exemplary procedure for the assay, whichmeasures the number of intact mitotic cells following drug applicationfollows.

Hepatocellular carcinoma cells (such as HepG2 or Hep3B) are seeded in a24-well plate at a density of 1.106/ml in 0.5 ml of culture medium, andincubated for 3 hours to allow time for cells to adhere. Cells aretreated with experimental compounds, 1 uM doxorubicin (1,2) or vehicle(DMSO) control for 120 hours after treatment. a) First remove culturesupernatant into 2 mL polypropylene tube and place on ice; b) Wash wellswith 0.5 mL PBS, transferring the wash volume to the 2 mL tubecontaining culture supernatant (floating cells). Keep cells on ice.Harvest by adding into the wells 200 uL of accutase for 5 min.Inactivate with 300 uL media. Pipette up and down to mix and transfertrypsinized cells from the well into the 2 mL tube with the floatingcells (total volume: 1.5 mL). Keep cells on ice. Spin cells 0.6 rcf for10 min at 4 degrees. Aspirate medium. Resuspend in 500 uL of Media byvortexing in pulses for about 15s. Keep cells on ice.

For cell counting: add 20 uL of cells to a plate after vortexing inpulses for 15s. Keep plate on ice. Then add 20 uL trypan blue rightbefore counting. Count cells with TC10 biorad cell counter. Spin cells0.6 rcf for 10 min at 4 degrees. Aspirate the medium carefully.Resuspend in 500 uL of annexin binding buffer 1× by vortexing. Transferthe cell suspension in a 5 ml FACS tube then add 5 ul of PropidiumIodide. Gently mix the cells and incubate for 15 min at RT in the dark.

For the flow cytometric analysis, unstained/untreated samples are usedat each time point as negative control, and doxorubicin treated samplesare used at each time point as a positive control. A FACScan flowcytometer is used, and FL2-A histograms are analyzed with FlowJosoftware.

Example 18

Diet Induced Obesity Studies

Compounds of the present invention are also assayed in high fat dietinduced obesity (DIO) studies. A representative protocol for the assayfollows.

The compounds of the present invention are readily adapted to clinicaluse as anti-obesity agents, insulin sensitizing agents,hyperinsulinemia-reversing agents, and hepatic steatosis-reversingagents. Such activity is determined by assessing the amount of testcompound that reduces body weight and percentage body fat, reducesplasma insulin levels, blunts the rise and/or accelerates the reductionin plasma insulin and glucose levels in response to an oral glucosechallenge, and reduces hepatic lipid content relative to a controlvehicle without test compound in mammals. Sprague Dawley rats are fedeither chow, a diet high in sucrose (for example AIN76A rodent diet;Research diets Inc. Cat #10001) or a diet high in fat (for exampleResearch diets Inc. Cat #12451), for from 3-8 weeks prior to and duringtest compound administration.

The anti-obesity, insulin sensitizing, hyperinsulinemia-reversing, andhepatic steatosis-reversing potential of compounds of the presentinvention are demonstrated by evaluating modifications to a variety ofparameters of lipid and carbohydrate metabolism using methods based onstandard procedures known to those skilled in the art. For example,after a 3-8 week period of ad libitum feeding of either a chow,high-fat, or high-sucrose diet, animals that continue to receive thediet are treated for 1-8 weeks with test compound administered either byoral gavage in water or saline or water or saline containing 0.5%methylcelulose using a Q.D., B.I.D, or T.I.D. dosing regimen. At varioustimes during study and at sacrifice (by CO₂ asphyxiation), blood iscollected either from the tail vein of an unanesthesized rat or from thevena cava of animals at sacrifice into heparin or EDTA containing tubesfor centrifugal separation to prepare plasma. Plasma levels ofparameters of lipid and carbohydrate metabolism known by those skilledin the art to be altered coincident with anti-obesity, insulinsensitizing, hyperinsulinemia-reversing, and hepatic steatosis-reversingactions, including but not limited to cholesterol and triglycerides,glucose, insulin, leptin, adiponectin, ketone bodies, free fatty acids,and glycerol, are measured using methods known to those skilled in theart.

The anti-obesity potential of compounds of the present invention canalso be demonstrated by evaluating their potential to produce areduction in body weight, a reduction in percentage body fat (measuredby for example dual-energy x-ray absorptiometry (DEXA) analysis), and areduction in plasma leptin levels. The anti-obesity and hepaticsteatosis-reversing potential of compounds of the present invention canalso be demonstrated by evaluating their potential to reduce theconcentration of triglycerides in the liver, using extraction andquantitation procedures known to those skilled in the art. The insulinsensitizing and hyperinsulinemia-reversing potential of compounds of thepresent invention can also be demonstrated by evaluating their potentialto blunt the rise and/or accelerate the reduction in plasma insulin andglucose levels in response to an oral glucose challenge, usingprocedures known to those skilled in the art.

The anti-obesity, insulin sensitizing, hyperinsulinemia-reversing, andhepatic steatosis-reversing potential of compounds of the presentinvention are assayed by administering compounds of the invention oncedaily by oral gavage in 0.5% methylcellulose in saline at doses of 0, 3,10, and 30 mg/kg to Sprague Dawley rats that have been consuming ahigh-fat diet for 4 weeks prior to initiation of dosing and continue toconsume the same high-fat diet throughout the 2-weeks of test compoundadministration. In some embodiments compounds of the invention produce adose-dependent reduction in total body weight relative tovehicle-treated control animals with no concomitant reduction in foodconsumption. The degree of body weight reduction paralleled plasma druglevels is measured at the end of the study. Plasma leptin levels, whichare known to be an indicator of whole-body fat mass and which areincreased by administration of the high-fat diet, are reduced bycompounds of the invention. The plasma leptin levels for animalsreceiving the standard chow diet (lean controls) are also evaluated todetermine the extent of parameter normalization produced by compounds ofthe invention. Plasma insulin levels, which are increased by a high-fatdiet, are reduced to near lean control levels by compounds of theinvention, with no concomitant reduction in plasma glucose levels,indicating an improvement in insulin sensitivity after treatment.Hepatic triglycerides, which are elevated by a high-fat diet, arereduced in a dose-dependent manner after administration of compounds ofthe invention, and in some embodiments are normalized to lean controllevels by the highest dose evaluated. In some embodiments, treatmentwith compounds of the invention does not increase either liver weight orthe markers of liver function, ALT and AST.

While we have described a number of embodiments of this invention, it isapparent that our basic examples may be altered to provide otherembodiments that utilize the compounds and methods of this invention.Therefore, it will be appreciated that the scope of this invention is tobe defined by the appended claims rather than by the specificembodiments that have been represented by way of example.

We claim:
 1. A compound of formula I-h:

or a pharmaceutically acceptable salt thereof, wherein: R¹ is hydrogenor C₁₋₄ aliphatic, optionally substituted with one or more halogens,—OR, —SR, —N(R)₂, —N(R)C(O)R, —C(O)N(R)₂, —N(R)C(O)N(R)₂, —N(R)C(O)OR,—OC(O)N(R)₂, —N(R)SO₂R, —SO₂RN(R)₂, —C(O)R, —C(O)OR, —OC(O)R, —C(O)OR,—S(O)R, or —SO₂R; R² is selected from 4-8 membered saturated orpartially unsaturated monocyclic heterocyclic ring having 1-2heteroatoms independently selected from nitrogen, oxygen, or sulfur, a5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, and an 8-10membered bicyclic heteroaromatic ring having 1-5 heteroatomsindependently selected from nitrogen, oxygen, or sulfur; L¹ is a 1-6membered straight or branched bivalent hydrocarbon chain optionallysubstituted with R⁵ and R^(5′); L² is a 1-6 membered straight orbranched bivalent hydrocarbon chain optionally substituted with R⁷ andR^(7′); R³ is halogen, —CN, —OR, —SR, —N(R)₂, —N(R)C(O)R, —C(O)N(R)₂,—C(O)N(R)S(O)₂R, —N(R)C(O)N(R)₂, —N(R)C(O)OR, —OC(O)N(R)₂, —N(R)SO₂R,—SO₂N(R)₂, —C(O)R, —C(O)OR, —OC(O)R, —S(O)R, —SO₂R, —B(OR)₂, or anoptionally substituted ring selected from phenyl or 5-6 memberedheteroaryl having 1-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur; R⁴ is hydrogen or a ring selected from a 3-8 memberedmonocyclic saturated or partially unsaturated carbocyclic ring, a 4-8membered monocyclic saturated or partially unsaturated heterocyclic ringhaving 1-2 heteroatoms independently selected from nitrogen, oxygen, orsulfur, phenyl, an 8-10 membered bicyclic aryl ring, a 5-6 memberedmonocyclic heteroaryl ring having 1-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclicheteroaryl ring having 1-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur; wherein said ring is optionally substitutedwith n instances of R⁸; each of R⁵ and R^(5′) is independently —R, —OR,—SR, —N(R)₂, —N(R)C(O)R, —C(O)N(R)₂, —N(R)C(O)N(R)₂, —N(R)C(O)OR,—OC(O)N(R)₂, —N(R)SO₂R, —SO₂N(R)₂, —C(O)R, —C(O)OR, —OC(O)R, —S(O)R, or—SO₂R; or R⁵ and R^(5′) are taken together to form a cyclopropylenyl,cyclobutylenyl, or oxetanyl group; each of R⁷ and R^(7′) isindependently, —R, —OR⁶, —SR, —N(R)₂, —N(R)C(O)R, —C(O)N(R)₂,—N(R)C(O)N(R)₂, —N(R)C(O)OR, —OC(O)N(R)₂, —N(R)SO₂R, —SO₂N(R)₂, —C(O)R,—C(O)OR, —OC(O)R, —S(O)R, —SO₂R, or —B(OR)₂; or R⁷ and R^(7′) are takentogether to form a 3-8 membered saturated or partially unsaturatedmonocyclic carbocyclic ring, or a 4-8 membered saturated or partiallyunsaturated monocyclic heterocyclic ring having 1-2 heteroatomsindependently selected from nitrogen, oxygen, or sulfur; R⁶ is —R,—C(O)N(R)₂, or —C(O)R; each R⁸ is independently selected from halogen,—R, —OR, —SR, —N(R)₂ or deuterium; each R is independently hydrogen,deuterium, or an optionally substituted group selected from C₁₋₆aliphatic, a 3-8 membered saturated or partially unsaturated monocycliccarbocyclic ring, phenyl, and 8-10 membered bicyclic aromaticcarbocyclic ring; a 4-8 membered saturated or partially unsaturatedmonocyclic heterocyclic ring having 1-2 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclicheteroaromatic ring having 1-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromaticring having 1-5 heteroatoms independently selected from nitrogen,oxygen, or sulfur; and n is 0-5.
 2. A composition comprising a compoundaccording to claim 1 and a pharmaceutically acceptable carrier,adjuvant, or vehicle.
 3. A compound of formula:

or a pharmaceutically acceptable salt thereof.